9-Substituted 8-Oxoadenine Compound

ABSTRACT

The present invention provides an 8-oxoadenine compound having immunomodulating activities such as an interferon inducing activity and useful as an antiviral agent and antiallergic agent, which is represented by the following formula (1): 
     
       
         
         
             
             
         
       
     
     [wherein the ring A represents a 6-10 membered aromatic carbocyclic ring and the like, R represents a halogen atom, an alkyl group and the like, n represents an integer of 0-2, Z 1  represents alkylene, X 2  represents oxygen atom, sulfur atom, SO 2 , NR 5 , CO, CONR 5 , NR 5 CO and the like, Y 1 , Y 2  and Y 3  represent independently a single bond or an alkylene group, X 1  represents oxygen atom, sulfur atom, NR 4  (R 4  is hydrogen atom or an alkyl group) or a single bond, R 2  represents a substituted or unsubstituted alkyl group, R 1  represents hydrogen atom, hydroxy group, an alkoxy group, an alkoxycarbonyl group or a haloalkyl group]
 
or its pharmaceutically acceptable salt.

This application is a continuation of U.S. application Ser. No.10/593,691 filed on Sep. 20, 2006, which is the National Stage under 35USC §371 of International Application Number PCT/JP2005/005401 filed onMar. 24, 2005, which claims priority under 35 USC §119 (a)-(d) ofApplication Number 2004-093672 filed in Japan on Mar. 26, 2004.

TECHNICAL FIELD

The present invention relates to a novel adenine compound useful as aprophylactic or therapeutic agent for viral diseases, allergic diseases,etc.

BACKGROUND ART

Interferon is an endogenous protein having an important role in animmune system in mammals, and not only takes a partial role in anonspecific defense mechanism in a living body but also stronglyparticipates in a specific defense mechanism thereof. Actually,interferon has been used as an agent for treating viral diseases such ashepatitis B and hepatitis C in a clinical field. A low molecular weightorganic compound (an interferon-inducing agent) which induces abiosynthesis of the said interferon has been developed as the nextgeneration interferon therapy, including an imidazoquinoline derivative(refer to the patent document 1) and an adenine derivative (refer to thepatent documents 2 and 3), and an imidazoquinoline derivative, Imiquimodhas been used as an external antiviral agent for genital wart in aclinical field.

On the other hand, T-cell taking a central role in an immune response ina living body is classified into two groups, Th1-cell and Th2-cell, andin a living body of a patient suffering from an allergic disease, anexcess amount of cytokines such as interleukin-4 (IL-4) andinterleukin-5 (IL-5) is excreted from Th-2 cell, and thus a compoundsuppressing an immune response of Th2 cell can be expected as an agentfor treating allergic diseases.

The above imidazoquinoline derivative and adenine derivative have beenknown as showing a suppressing activity of production of interleukin-4(IL-4) and interleukin-5 (IL-5) as well as an inducing activity ofinterferon, and have been actually known to be effective to an allergicdisease also in a model animal.

However, there is such a fear that systemic adverse effects based on theinterferon inducing activity would be problem upon using suchderivatives as an anti-allergic agent.

-   [Patent Document 1] U.S. Pat. No. 4,689,338-   [Patent Document 2] WO 98/01448-   [Patent Document 3] WO 99/28321

DISCLOSURE OF INVENTION

The problem to be solved by the present invention is to provide a novel8-oxoadenine compound useful as an immuno-modulator and a therapeutic orprophylactic agent for allergic diseases, viral diseases and cancerscomprising the said compound as an effective ingredient.

The present inventors have made extensive study for obtaining animmuno-modulator useful as a therapeutic or a prophylactic agent forallergic diseases such as asthma, viral diseases and cancers to find the8-oxoadenine compound of the present invention. Namely, the compound ofthe present invention is an immuno-modulator having an immunoactivationeffect such as an interferon inducing activity and also having asuppressing activity of production of a cytokine such as IL-4 and IL-5originated from Th2-cell, and thus is effective as a therapeutic orprophylactic agent for allergic diseases, viral diseases and cancers.

The prevent invention has been completed on the basis of the abovefinding.

BEST MODE FOR CARRYING OUT THE INVENTION

Namely, the present invention is as follows:

[1] An 8-oxoadenine compound shown by the formula (1):

wherein ring A represents a 6-10 membered aromatic carbocyclic ring or a5-10 membered heteroaromatic ring;

R represents a halogen atom, an alkyl group, a hydroxyalkyl group, ahaloalkyl group, an alkoxy group, a hydroxyalkoxy group, a haloalkoxygroup, amino group, an alkylamino group, a dialkylamino group, or acyclic amino group;n represents an integer of 0-2, and when n is 2, the Rs may be the sameor different;Z¹ represents a substituted or unsubstituted alkylene group or asubstituted or unsubstituted cycloalkylene group;X² represents oxygen atom, sulfur atom, SO₂, NR⁵, CO, CONR⁵, NR⁵CO,SO₂NR⁵, NR⁵SO₂, NR⁵CONR⁶ or NR⁵CSNR⁶ (in which R⁵ and R⁶ are eachindependently hydrogen atom, a substituted or unsubstituted alkyl group,or a substituted or unsubstituted cycloalkyl group.);Y¹, Y² and Y³ represent each independently a single bond or an alkylenegroup;X¹ represents oxygen atom, sulfur atom, SO₂, NR⁴ (wherein R⁴ is hydrogenatom or an alkyl group) or a single bond;R² represents hydrogen atom, a substituted or unsubstituted alkyl group,a substituted or unsubstituted alkenyl group, a substituted orunsubstituted alkynyl group or a substituted or unsubstituted cycloalkylgroup; andR¹ represents hydrogen atom, hydroxy group, an alkoxy group, analkoxycarbonyl group, a haloalkyl group, a haloalkoxy group, asubstituted or unsubstituted aryl group, a substituted or unsubstitutedheteroaryl group or a substituted or unsubstituted cycloalkyl group, orits pharmaceutically acceptable salt.[2] The 8-oxoadenine compound as described in the above [1], whereinring A represents a 6-10 membered aromatic carbocyclic ring, or a 5-10membered heteroaromatic ring containing 1-4 hetero atoms selected from0-4 nitrogen atoms, 0-2 oxygen atoms and 0-2 sulfur atoms;R represents a halogen atom, an alkyl group of 1-6 carbons, ahydroxyalkyl group of 1-6 carbon, a haloalkyl group of 1-6 carbons, analkoxy group of 1-6 carbons, a hydroxyalkoxy group of 1-6 carbons, ahaloalkoxy group of 1-6 carbons, amino group, an alkylamino group of 1-6carbons, a dialkylamino group in which each alkyl moiety has 1-6carbons, and a cyclic amino group, n is an integer of 0-2, and when n is2, R⁵ may be the same or different;Z¹ represents an alkylene group of 1-6 carbons or a cycloalkylene groupof 3-8 carbons, which is optionally substituted by hydroxy group;X² represents oxygen atom, sulfur atom, SO₂, NR⁵, CO, CONR⁵, NR⁵CO,SO₂NR⁵, NR⁵SO₂, NR⁵CONR⁶ or NR⁵CSNR⁶ (in which R⁵ and R⁶ areindependently hydrogen atom, a substituted or unsubstituted alkyl groupof 1-6 carbons and a substituted or unsubstituted cycloalkyl group of3-8 carbons, wherein the substituents of the alkyl group or cycloalkylgroup are selected from a halogen atom, hydroxy group, an alkoxy groupof 1-6 carbons, carboxy group, an alkoxycarbonyl group of 2-5 carbons,carbamoyl group, amino group, an alkylamino group of 1-6 carbons, adialkylamino group in which each alkyl moiety has 1-6 carbons, a cyclicamino group, carboxy group and tetrazolyl group which may be substitutedby an alkyl group of 1-6 carbons.);Y¹, Y² and Y³ represent independently a single bond or an alkylene groupof 1-6 carbons;X¹ represents oxygen atom, sulfur atom, SO₂, NR⁴ (wherein R⁴ representshydrogen atom or an alkyl group), or a single bond;R² represents a substituted or unsubstituted alkyl group of 1-6 carbons,a substituted or unsubstituted alkenyl group of 2-6 carbons, asubstituted or unsubstituted alkynyl group of 2-6 carbons or asubstituted or unsubstituted cycloalkyl group of 3-8 carbons (whereinthe substituent in the alkyl group, the alkenyl group and the alkynylgroup is selected from a halogen atom, hydroxy group, an alkoxy group of1-6 carbons, an acyloxy group of 2-10 carbons, amino group, analkylamino group of 1-6 carbons and a dialkylamino group in which eachalkyl moiety has 1-6 carbons, and a cyclic amino group.);R¹ represents hydrogen atom, hydroxy group, an alkoxy group of 1-6carbons, an alkoxycarbonyl group of 2-5 carbons, a haloalkyl group of1-6 carbons, a haloalkoxy group of 1-6 carbons, a substituted orunsubstituted aryl group of 6-10 carbons, a substituted or unsubstituted5-10 membered heteroaryl group containing 1-4 hetero atoms selected from0-4 nitrogen atoms, 0-2 oxygen atoms or 0-2 sulfur atoms or asubstituted or unsubstituted cycloalkyl group of 3-8 carbons, andthe said substituent in the aryl group, the heteroaryl group and thecycloalkyl group is selected from a halogen atom, hydroxy group, analkyl group of 1-6 carbons, a haloalkyl group of 1-6 carbons, an alkoxygroup of 1-6 carbons, a haloalkoxy group of 1-6 carbons, analkylcarbonyl group of 2-5 carbons, amino group, an alkylamino group of1-6 carbons and a dialkylamino group in which each alkyl moiety has 1-6carbons,and the said cyclic amino group means a 4-7 membered saturated cyclicamino group containing 1-2 hetero atoms selected from 1-2 nitrogenatoms, 0-1 oxygen atom and 0-1 sulfur atom, which may be substitutedwith a halogen atom, hydroxy group, oxo group, an alkyl group of 1-6carbons, an alkoxy group of 1-6 carbons, an alkylcarbonyl group of 2-5carbons or an alkoxycarbonyl group of 2-5 carbons, in the formula (1),or its pharmaceutically acceptable salt.[3] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in the above of the above [1] or [2], wherein X² in theformula (1) is oxygen atom, sulfur atom, NR⁵, SO₂, NR⁵SO₂ or NR⁵CONR⁶.[4] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1] to [3], wherein Y³ in the formula (1)is a single bond, methylene or ethylene.[5] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1] to [4], wherein Z¹ in the formula (1)is a straight chained alkylene group of 1-6 carbons which may besubstituted with hydroxy group.[6] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1]-[5], wherein X¹ in the formula (1) isoxygen atom or sulfur atom.[7] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1]-[6], wherein Y¹ in the formula (1) isa single bond or an alkylene group of 1-6 carbons.[8] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1]-[7], wherein R¹ in the formula (1) ishydrogen atom, an alkoxycarbonyl group, hydroxy group, or an alkoxygroup.[9] The 8-oxoadenine compound or its pharmaceutically acceptable salt asdescribed in any of the above [1]-[8], wherein a group shown by theformula (2) in the formula (1):

wherein ring A, R, n, Y³ and R² have the same meaning as in the formula(1), is a group shown by the formula (3) or the formula (4):

wherein R, n and R² have the same meaning as in the formula (1), and R³is hydrogen atom or an alkyl group.

[10] The 8-oxoadenine compound or its pharmaceutically acceptable saltas described in the above [9], wherein R² is methyl group or an alkylgroup of 2-6 carbons substituted by a dialkylamino group or a cyclicamino group.[11] The 8-oxoadenine compound or its pharmaceutically acceptable saltas described in the above [9] or [10], wherein R³ is hydrogen atom.[12] A pharmaceutical composition, comprising the 8-oxoadenine compoundor its pharmaceutically acceptable salt described in any of the above[1]-[11] as an active ingredient.[13] An immuno-modulator, comprising the 8-oxoadenine compound or itspharmaceutically acceptable salt described in any of the above [1]-[11]as an active ingredient.[14] A therapeutic or prophylactic agent for viral diseases, cancers orallergic diseases, comprising the 8-oxoadenine compound or itspharmaceutically acceptable salt described in any of the above [1]-[11]as an active ingredient.[15] A medicament for topical administration, comprising the8-oxoadenine compound or its pharmaceutically acceptable salt describedin any of the above [1]-[11] as an active ingredient.[16] A use of the 8-oxoadenine compound or its pharmaceuticallyacceptable salt described in any of the above [1]-[11] as a medicament.[17] A use of the 8-oxoadenine compound or its pharmaceuticallyacceptable salt described in any of the above [1]-[11] for manufacturingan immuno-modulator.[18] A use of the 8-oxoadenine compound or its pharmaceuticallyacceptable salt described in any of the above [1]-[11] for manufacturinga therapeutic or prophylactic agent for viral diseases, cancers andallergic diseases.[19] A method for modulating immune response which comprisesadministering to a patient, an effective amount of the 8-oxoadeninecompound or its pharmaceutically acceptable salt described in any of theabove [1]-[11].[20] A method for treating or preventing viral diseases, cancers andallergic diseases which comprises administering to a patient, aneffective amount of the 8-oxoadenine compound or its pharmaceuticallyacceptable salt described in any of the above [1]-[11].[21] A process for preparing the 8-oxoadenine compound as described inany of the above [1]-[11] which comprises brominating a compound shownby the formula (10):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ are the samedefined in the above [1],

reacting the resultant with a metal alkoxide and then hydrolyzing, orhydrolyzing the resultant.[22] A compound shown by the formula (10):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ are the samedefined in the above [1].

[23] A process for preparing an 8-oxoadenine compound as described inany of the above [1]-[11] which comprises deprotecting a compound shownby the formula (11):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ are the samedefined in the above [1].

[24] A compound shown by the formula (11):

wherein Ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ are the samedefined in the above [1].

[25] A compound or a pharmaceutically acceptable salt thereof selectedfrom the group consisting of the following compounds:

-   2-Butoxy-8-oxo-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(3-methoxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(2-methoxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(4-methoxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(4-methoxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-{2-[4-(2-methoxycarbonylethyl)phenoxy]ethyl}adenine,-   2-Butoxy-8-oxo-9-[4-(3-methoxycarbonylbenzenesulfonamide)butyl]adenine,-   2-Butoxy-8-oxo-9-[4-(3-methoxycarbonylmethylbenzenesulfonamide)butyl]adenine,-   2-Butoxy-8-oxo-9-[4-(3-methoxycarbonylphenylaminocarbonylamino)butyl]adenine,-   2-Butoxy-8-oxo-9-[4-(3-methoxycarbonylmethylphenylaminocarbonylamino)-butyl]adenine,-   Methyl    [3-({[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}methyl)phenyl]acetate,-   [3-({[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}methyl)phenyl]acetic    acid,-   Methyl    3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate,-   3-({[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoic    acid,-   Methyl    4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate,-   4-({[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoic    acid,-   Methyl    (3-{[[3-(6-amino-2-butoxy-8-oxo-9H-purin-9-yl)propyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}methyl)phenyl]acetate,-   Ethyl    2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate,-   3-(Dimethylamino)propyl    2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate,-   Methyl    3-[4-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}sulfonyl)phenyl]propanoate,-   3-[4-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}sulfonyl)phenyl]propanoic    acid,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-pyrrolidin-1-ylethyl)amino]sulfonyl}phenyl)acetate,-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-pyrrolidin-1-ylethyl)amino]sulfonyl}phenyl)acetic    acid,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]    (2-methoxyethyl)amino]sulfonyl}phenyl)acetate,-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-methoxy-ethyl)amino]sulfonyl}phenyl)acetic    acid,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](methyl)amino]sulfonyl}phenyl)acetate-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](methyl)amino]sulfonyl}phenyl)acetic    acid,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)phenyl]acetate,-   [3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)phenyl]acetic    acid,-   Methyl    [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}sulfonyl)phenyl]acetate,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxy-2-methylpropyl)amino]sulfonyl}phenyl)acetate,-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxy-2-methylpropyl)amino]sulfonyl}phenyl)acetic    acid,-   Methyl    [3-({[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}sulfonyl)phenyl]acetate,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][(2R)-2,3-dihydroxypropyl]amino}sulfonyl)phenyl]acetate,-   [3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][(2R)-2,3-dihydroxypropyl]amino}sulfonyl)phenyl]acetic    acid,-   Methyl    3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)benzoate,-   3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethyl-amino)-2,2-dimethylpropyl]amino}sulfonyl)benzoic    acid,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate,-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetic    acid,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}methyl)phenyl]acetate,-   [3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}methyl)phenyl]acetic    acid,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl)phenyl]acetate,-   [3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl)phenyl]acetic    acid,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate,-   (3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetic    acid,-   Methyl    (3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate,-   Methyl    [3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][2-(1H-tetrazol-5-yl)ethyl]amino}methyl)phenyl]acetate,-   Methyl    (3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)acetate,-   (3-{[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)acetic    acid,-   Methyl    (3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}phenyl)acetate,-   Methyl    (3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}phenyl)acetate,-   (3-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}phenyl)acetic    acid,-   Methyl    [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate,-   ([3-({[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetic    acid,-   Methyl    (3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]    (2-methoxyethyl)amino]methyl}phenyl)acetate,-   (3-{[[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]    (2-methoxyethyl)amino]methyl}phenyl)acetic acid,-   Methyl    (3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]sulfonyl}phenyl)acetate,-   Methyl    (3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](methyl)amino]methyl}phenyl)acetate,-   (3-{[[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](methyl)amino]methyl}phenyl)acetic    acid,-   Methyl    4-[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)-2-hydroxypropoxy]benzoate,-   Methyl    (3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]    (2-hydroxyethyl)amino]methyl}phenyl)acetate,-   Methyl    (3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]    (2-hydroxyethyl)amino]methyl}phenyl)acetate,-   2-Butoxy-8-oxo-9-[2-(3-hydroxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(3-hydroxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(2-hydroxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(4-hydroxycarbonylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-[2-(4-methoxycarbonylmethylphenoxy)ethyl]adenine,-   2-Butoxy-8-oxo-9-{2-[4-(2-hydroxycarbonylethyl)phenoxy]ethyl}adenine,-   2-Butoxy-8-oxo-9-[4-(3-hydroxycarbonylbenzenesulfonamide)butyl]adenine,-   2-Butoxy-8-oxo-9-[4-(3-hydroxycarbonylmethylbenzenesulfonamide)butyl]adenine,-   2-Butoxy-8-oxo-9-[4-(3-hydroxycarbonylphenylaminocarbonylamino)butyl]adenine,    and-   2-Butoxy-8-oxo-9-[4-(3-hydroxycarbonylmethylphenylaminocarbonylamino)butyl]adenine.

The present invention is explained below further in details.

“Halogen atom” is exemplified by fluorine, chlorine, bromine and iodine,among which fluorine and chlorine are preferable.

“Alkyl group” is exemplified by a straight chained or branched alkylgroup of 1-10 carbons, including specifically methyl group, ethyl group,propyl group, 1-methylethyl group, butyl group, 2-methylpropyl group,1-methylpropyl group, 1,1-dimethylethyl group, pentyl group,3-methylbutyl group, 2-methylbutyl group, 2,2-dimethylpropyl group,1-ethylpropyl group, 1,1-dimethylpropyl group, hexyl group,4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group,1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group,1-methylhexyl group, 1-ethylpentyl group, octyl group, 1-methylheptylgroup, 2-ethylhexyl group, nonyl group and decyl group, among which analkyl group of 1-6 carbons is preferable and an alkyl group of 1-4carbons is further preferable.

“Cycloalkyl group” is exemplified by a 3-8 membered monocycliccycloalkyl group, including specifically cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group andcyclooctyl group.

“Alkenyl group” is exemplified by a straight chained or branched alkenylgroup of 2-8 carbons having 1-3 double bonds, including specificallyethenyl group, 1-propenyl group, 2-propenyl group, 1-methyl-ethenylgroup, 1-butenyl group, 2-butenyl group, 3-butenyl group,2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group,4-pentenyl group, 3-methyl-2-butenyl group, 1-hexenyl group, 2-hexenylgroup and 1-octenyl group, among which an alkenyl group of 2-4 carbonsis preferable.

“Alkynyl group” is exemplified by a straight chained or branched alkynylgroup of 2-8 carbons having 1 or 2 triple bonds, including specificallyethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group,2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 1-pentynylgroup, 2-pentynyl group, 3-pentynyl group, 5-pentynyl group,1-methyl-3-butynyl group, 1-hexynyl group, and 2-hexynyl group, amongwhich an alkynyl group of 2-4 carbons is preferable.

“Alkylene” is exemplified by a straight chained or branched alkylenegroup of 1-6 carbons, including specifically methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,methylmethylene, ethylmethylene, propylethylene, 1-methylethylene,2-methylethylene, 1-methyltrimethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 2-methyltetramethylene and3-methylpentamethylene.

“Cycloalkylene” is exemplified by a cycloalkylene of 3-8 carbons, whichis a divalent group of a cycloalkane in the above mentioned cycloalkylgroup, including specifically 1,2-cyclopropylene, 1,3-cyclobutylene,1,2-cyclobutylene, 1,3-cyclopentylene, 1,2-cyclopentylene,1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene,1,4-cycloheptylene and 1,5-cyclooctylene.

“Alkoxy group” is exemplified by a straight chained or branched alkoxygroup of 1-10 carbons, including specifically methoxy group, ethoxygroup, propoxy group, 1-methylethoxy group, butoxy group,2-methylpropoxy group, 1-methylpropoxy group, 1,1-dimethylethoxy group,pentoxy group, 3-methylbutoxy group, 2-methylbutoxy group,2,2-dimethylpropoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxygroup, hexyloxy group, 4-methylpentyloxy group, 3-methylpentyloxy group,2-methylpentyloxy group, 1-methylpentyloxy group, 3,3-dimethylbutoxygroup, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, heptyloxy group, 1-methylhexyloxy group,1-ethylpentyloxy group, octyloxy group, 1-methylheptyloxy group,2-ethylhexyloxy group, nonyloxy group and decyloxy group, among which analkoxy group of 1-6 carbons is preferable, and an alkoxy group of 1-4carbons is further preferable.

“Alkyl moiety” in “alkylcarbonyl group” is exemplified by the same asthe above mentioned alkyl group. Preferable alkylcarbonyl group is astraight chained or branched alkylcarbonyl group of 2-5 carbons,including specifically acetyl group, propanoyl group, butanoyl group and2-methylpropanoyl group.

“Alkoxy moiety” in “alkoxycarbonyl group” is exemplified by the same asthe above mentioned alkoxy group. Preferable alkoxycarbonyl group is astraight chained or branched alkoxycarbonyl group of 2-5 carbons,including specifically methoxycarbonyl group, ethoxycarbonyl group,propoxycarbonyl group, 2-methylethoxycarbonyl group, butoxycarbonylgroup and 2-methylpropoxycarbonyl group.

“Alkyl moiety” in “hydroxyalkyl group” is exemplified by the same as theabove mentioned alkyl group. A hydroxyalkyl group includes specifically2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group and2-hydroxypropyl group.

“Haloalkyl group” is exemplified by an alkyl group substituted by thesame or different, 1-9 halogen atoms, preferably 1-5 halogen atoms,including specifically trifluoromethyl group, 2,2,2-trifluoroethylgroup, 2,2-difluoroethyl group and pentafluoroethyl group.

“Alkoxy moiety” in “hydroxyalkoxy group” is exemplified by the same asthe above mentioned alkoxy group. A hydroxyalkoxy group includesspecifically 2-hydroxyethoxy group, 3-hydroxypropoxy group,4-hydroxybutoxy group and 2-hydroxypropoxy group.

“Haloalkoxy group” is exemplified by an alkoxy group substituted by thesame or different, 1-9 halogen atoms, preferably 1-5 halogen atoms,including specifically trifluoromethoxy group, 2,2,2-trifluoroethoxygroup, 2,2-difluoroethoxy group and pentafluoroethoxy group.

“Alkyl moiety” in “alkylamino group” is exemplified by the same as theabove mentioned alkyl group as above. Preferable alkylamino group is astraight chained or branched alkylamino group of 1-4 carbons, includingspecifically methylamino group, ethylamino group, propylamino group,2-methylethylamino group and butylamino group.

Two alkyl moieties in “dialkylamino group” may be the same or different,and the alkyl moiety is exemplified by the same as the above mentionedalkyl group. Preferable dialkylamino group is a straight chained orbranched dialkylamino group in which each alkyl moiety has 1-4 carbons,including specifically dimethylamino group, diethylamino group,dipropylamino group, methylethylamino group, methylpropylamino group andethylpropylamino group.

“Cyclic amino group” is exemplified by a saturated 4-7 membered cyclicamino group containing 1-2 hetero atoms selected from 1-2 nitrogenatoms, 0-1 oxygen atom and 0-1 sulfur atom, including specificallyazetidinyl group, piperidinyl group, piperazinyl group, morpholino groupand thiomorpholino group. The cyclic amino group may be substituted witha halogen atom, hydroxy group, oxo group, an alkyl group, an alkoxygroup, an alkylcarbonyl group or an alkoxycarbonyl group.

“Aryl group” is exemplified by a 6-10 membered aryl group, includingspecifically phenyl group, 1-naphthyl group and 2-naphthyl group.

“Heteroaryl group” is exemplified by a 5-10 membered mono or bicyclicheteroaryl group containing 1-4 hetero atoms selected from 0-2 nitrogenatoms, 0-1 oxygen atom and 0-1 sulfur atom, including specifically furylgroup, thienyl group, pyrrolyl group, pyridyl group, indolyl group,isoindolyl group, quinolyl group, isoquinolyl group, pyrazolyl group,imidazolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group,thiazolyl group and oxazolyl group. The bonding site in the heteroarylgroup is not specifically limited and it may be on any of the nitrogenor carbon atoms.

“6-10 Membered aromatic carbocyclic ring” shown by ring A in the formula(1) is exemplified by benzene ring and naphthalene ring.

“5-10 Membered heteroaromatic ring” shown by ring A is exemplified by a5-10 membered monocyclic or bicyclic heteroaromatic ring containing 1-4hetero atoms selected from 0-4 nitrogen atoms, 0-2 oxygen atoms and 0-2sulfur atoms, including specifically pyrrole ring, furan ring, thiophenering, pyrazole ring, imidazole ring, oxazole ring, thiazole ring,isoxazole ring, isothiazole ring, pyridine ring, pyridazine ring,pyrimidine ring, pyrazine ring, triazine ring, quinoline ring,isoquinoline ring, indole ring, benzofuran ring, benzothiophene ring,indazole ring, benzoisoxazole ring, benzoisothiazole ring,benzoimidazole ring, benzoxazole ring, benzothiazole ring, phthalazinering, quinazoline ring and quinoxaline ring.

The bonding site in the heteroaromatic ring is not specifically limitedand it may be on any of the nitrogen or carbon atoms. Preferableheterocyclic ring shown by ring A is pyridine ring, furan ring,thiophene ring, pyrrole ring, indole ring and oxazole ring, furtherpreferable one is pyridine ring, furan ring and thiophene ring.

The group shown by the formula (2):

wherein ring A, R, n, Y³ and R² are the same defined in the above,

is preferably one selected from the group consisting of followingformulas (3) to (9):

wherein n, R and R² have the same meaning as above, and R³ is a hydrogenatom or an alkyl group, preferably hydrogen atom.

In the formula (1), R is preferably exemplified by a halogen atom suchas fluorine atom and chlorine atom, an alkyl group of 1-4 carbons suchas methyl group and ethyl group, an alkoxy group of 1-4 carbons such asmethoxy group and ethoxy group, a haloalkyl group of 1-2 carbons such astrifluoromethyl group, difluoromethyl group and 2,2,2-trifluoroethylgroup, a haloalkoxy group of 1-2 carbons such as trifluoromethoxy group,difluoromethoxy group and 2,2,2-trifluoroethoxy group, a dialkylaminogroup of 1-5 carbons such as dimethylamino group, diethylamino group,ethylmethylamino group and dipropylamino group, and a cyclic amino groupsuch as morpholino group, piperidino group, piperazino group andpyrrolidino group, and the cyclic amino group may be substituted with ahalogen atom, hydroxy group, an alkyl group, an alkoxy group, analkylcarbonyl group or an alkoxycarbonyl group.

In the formula (1), n is preferably 0 or 1.

In the substituted or unsubstituted alkyl group, the substituted orunsubstituted alkenyl group, the substituted or unsubstituted alkynylgroup and the substituted or unsubstituted cycloalkyl group shown by R²in the formula (1), the substituent is exemplified by a halogen atom,hydroxy group, an alkoxy group, an acyloxy group, amino group, analkylamino group, a dialkylamino group and a cyclic amino group.

The acyloxy group is exemplified by acyloxy group of 2-10 carbons,including a substituted or unsubstituted alkylcarbonyloxy group of 2-5carbons, a substituted or unsubstituted alkenylcarbonyloxy group of 2-5carbons, a substituted or unsubstituted alkynylcarbonyloxy group of 2-5carbons, a substituted or unsubstituted arylcarbonyloxy group and asubstituted or unsubstituted heteroarylcarbonyloxy group. The alkyl,alkenyl and alkynyl in the above alkylcarbonyloxy group,alkenylcarbonyloxy group and alkynylcarbonyloxy group are exemplified bythe same as the above mentioned alkyl group, alkenyl group and alkynylgroup, respectively.

The substituent in the substituted alkylcarbonyloxy group,alkenylcarbonyloxy group and alkynylcarbonyloxy group is exemplified bya halogen atom, hydroxy group, an alkoxy group and an aryl group.

The aryl moiety in the above arylcarbonyloxy group is exemplified by thesame as the above mentioned aryl group. The heteroaryl in the aboveheteroarylcarbonyloxy group is exemplified by the same as the abovementioned heteroaryl group. The substituent in the above substitutedaryl group and heteroaryl group is exemplified by a halogen atom,hydroxy group, an alkoxy group, a haloalkyl group, a haloalkoxy group,an alkylcarbonyl group, amino group, an alkylamino group and adialkylamino group.

The substituent in the substituted or unsubstituted alkyl group in thegroups R⁵ and R⁶ in the formula (1) is exemplified by a halogen atom,hydroxy group, an alkoxy group, a carboxy group, an alkoxycarbonylgroup, carbamoyl group, an alkylamino group, a dialkylamino group, acyclic amino group, carboxy group and tetrazolyl group which may besubstituted by an alkyl group, wherein the groups R⁵ and R⁶ may besubstituted with one or more substituents, preferably 1-3 substituents.

The cyclic amino group includes specifically piperidino group,piperazino group, pyrrolidino group, morpholino group, thiomorpholinogroup, pyrrolidon-1-yl group and succinimide-1-yl group,4-hydroxypiperidino group and 4-methylpiperidino group.

R² is preferably hydrogen atom, an alkyl group of 1-4 carbons, anacyloxyalkyl group, or an alkyl group of 1-6 carbons substituted byamino group, an alkylamino group, a dialkylamino group or a cyclic aminogroup. The acyloxyalkyl group is exemplified specifically byacetoxymethyl group, 1-acetoxyethyl group and benzoyloxymethyl group.Further preferably, R² is methyl group, or an alkyl group of 1-4 carbonssubstituted by amino group, an alkylamino group, a dialkylamino group ora cyclic amino group.

The compound in the formula (1) wherein R² represents hydrogen atom isalso useful as the synthetic intermediate of the compound wherein R²represents except hydrogen atom. The compound in the formula (1) whereinR² represents hydrogen atom is also useful as a reagent for testingpharmacokinetics of the compound wherein R² represents except hydrogenatom because the former corresponds to a metabolite of the latter.

In the formula (1), Y² is preferably a single bond or a straight chainedalkylene group of 1-4 carbons, including specifically methylene,ethylene, trimethylene and tetramethylene.

In the formula (1), Y³ is preferably a single bond or a straight chainedor branched alkylene of 1-4 carbons, including specifically methylene,ethylene, trimethylene, tetramethylene and methylmethylene.

In the formula (1), X² is preferably oxygen atom, NHSO₂, NHCONH and NR⁵.

In the formula (1), Z¹ is preferably a straight chained or branchedalkylene of 1-5 carbons, including specifically methylene, ethylene,trimethylene, tetramethylene and pentamethylene, 2-methylmethylene,2-methylethylene, 1-methylethylene, 2-methylpropylene and2,2-dimethylpropylene. Still further preferably Z¹ is ethylene,trimethylene and tetramethylene. The alkylene may be substituted byhydroxy group, oxo group, etc.

In the formula (1), when X¹ is NR⁴, R⁴ is preferably hydrogen atom andan alkyl group of 1-3 carbons, more preferably hydrogen atom and methylgroup. X¹ is preferably oxygen atom and sulfur atom, more preferablyoxygen atom.

In the formula (1), Y¹ is preferably alkylene of 1-6 carbons, includingspecifically methylene, ethylene, trimethylene, tetramethylene,pentamethylene and heptamethylene, more preferably a straight chainedalkylene of 1-5 carbons.

In the formula (1), R¹ is preferably hydrogen atom, hydroxy group, astraight chained or branched alkoxy group of 1-4 carbons, a straightchained or branched alkoxycarbonyl group of 2-5 carbons, a haloalkylgroup of 1 or 2 carbons, a haloalkoxy group of 1 or 2 carbons and asubstituted or unsubstituted aryl group. The aryl group is preferablyphenyl group.

The substituent in the substituted aryl group and the substitutedheteroaryl group is exemplified by a halogen atom, hydroxy group, analkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, analkylcarbonyl group, amino group, an alkylamino group and a dialkylaminogroup.

More preferably R¹ is hydrogen atom, hydroxy group, a straight chainedor branched alkoxy group of 1-4 carbons and a straight chained orbranched alkoxycarbonyl group of 2-5 carbons.

The above alkoxy group is specifically exemplified by methoxy group andethoxy group. The above alkoxycarbonyl group is specifically exemplifiedby methoxycarbonyl group and ethoxycarbonyl group. The above haloalkylgroup is specifically exemplified by trifluoromethyl group. The abovehaloalkoxy group is specifically exemplified by trifluoromethoxy group.

The adenine compound of the present invention, in accordance with thekind of the substituent includes all tautomers, geometrical isomers,stereoisomers, and a mixture thereof.

Namely, in a case where there are one or more asymmetrical carbons inthe compound of the formula (1), there exist diastereomers and opticalisomers, and mixtures of those diastereomers and optical isomers andseparated ones are also included in the present invention.

Additionally, the adenine compound shown by the formula (1) and itstautomers are chemically equivalent, and the adenine compound of thepresent invention includes the tautomers. The tautomer is specifically ahydroxy compound shown by the formula (1′):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above.

The pharmaceutically acceptable salt is exemplified by an acid salt anda base salt. The acid salt is, for example, an inorganic acid salt suchas hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate andphosphate, and an organic acid salt such as citrate, oxalate, acetate,formate, propionate, benzoate, trifluoroacetate, maleate, tartrate,methanesulfonate, benzenesulfonate and p-toluenesulfonate, and the basesalt is exemplified by an inorganic base salt such as sodium salt,potassium salt, calcium salt, magnesium salt and ammonium salt, and anorganic base salt such as triethylammonium salt, triethanolammoniumsalt, pyridinium salt and diisopropylammonium salt, and further a basicor acidic amino acid salt such as arginine salt, aspartic acid salt andglutamic acid salt. The compound shown by the formula (1) may be hydrateand a solvate such as ethanolate.

The compound shown by the formula (1) can be prepared by the followingmethods. The starting compounds not disclosed in the below can beprepared by a similar method to the following method or by a knownmethod or its similar method.

Preparation Method 1

, wherein L represents a leaving group, and R¹, Y¹, X¹ and Z¹ have thesame meanings as above, and X³ is a group shown by the followingformula:

(wherein ring A, n, R, R², X², Y² and Y³ have the same meanings asabove), a leaving group, amino group, hydroxy group, mercapto group,carboxy group or sulfonic acid group.

The compound (II) can be obtained by reacting the compound (I) with thecompound (IX) in the presence of a base.

As the base, use can be made of an alkali metal carbonate such as sodiumcarbonate and potassium carbonate, an alkaline earth metal carbonatesuch as calcium carbonate, a metal hydroxide such as sodium hydroxideand potassium hydroxide, a metal hydrogenate such as sodium hydride, ametal alkoxide such as potassium t-butoxide. As the solvent, use can bemade of a halogenated hydrocarbon such as carbon tetrachloride,chloroform and methylene chloride, an ether such as diethyl ether,tetrahydrofuran and 1,4-dioxane, and an aprotic solvent such asdimethylformamide, dimethyl sulfoxide and acetonitrile. The reactiontemperature is selected from a range of about 0° C. to around theboiling point of the solvent.

The compound (III) can be obtained by brominating the compound (II). Asthe brominating agent, use can be made of bromine, hydroperbromic acidand N-bromosuccinimide. In this reaction, a reaction auxiliary such assodium acetate may be added. As the solvent, use can be made of ahalogenated hydrocarbon such as carbon tetrachloride, methylene chlorideand dichloroethane, ether such as diethyl ether, acetic acid and carbondisulfide. The reaction temperature is selected from a range of about 0°C. to around the boiling point of the solvent.

The compound (VI) can be obtained by reacting the compound (III) with ametal alkoxide such as sodium methoxide, followed by treating underacidic conditions.

As the solvent on reacting with the metal alkoxide, use is made of anether such as diethyl ether, tetrahydrofuran and 1,4-dioxane, an aproticsolvent such as dimethylformamide and an alcohol such as methanolcorresponding to the metal alkoxide used. The reaction temperature isselected from a range of room temperature to around the boiling point ofthe solvent.

As the acid to be used in the acid treatment, use can be made of aninorganic acid such as hydrochloric acid, hydrobromic acid and sulfuricacid and an organic acid such as trifluoroacetic acid. As the solvent,use is made of ether such as diethyl ether and tetrahydrofuran, anaprotic solvent such as dimethylformamide and acetonitrile and analcohol such as methanol and ethanol. The reaction temperature isselected from a range of room temperature to around the boiling point ofthe solvent.

The compound (VIII) can be obtained by reacting the compound (VI) withthe compound (X).

In a case where X¹ is NR⁴, the reaction is conducted in the presence orabsence of a base. As the base, use can be made of an alkali metalcarbonate such as sodium carbonate and potassium carbonate, an alkalineearth metal carbonate such as calcium carbonate, a metal hydroxide suchas sodium hydroxide and potassium hydroxide and an organic base such astriethylamine, diisopropylethylamine and 4-dimethylamino pyridine. Asthe solvent, use can be made of an ether such as tetrahydrofuran,1,4-dioxane and diglyme, an alcohol such as propanol and butanol and anaprotic solvent such as dimethylformamide. The reaction temperature isselected from a range of about 50° C. to about 200° C. The reaction maybe carried out in the absence of a solvent.

In a case where X¹ is oxygen atom or sulfur atom, the reaction isconducted in the presence of a base. As the base, use can be made of analkali metal such as sodium and potassium and an alkali metal hydridesuch as sodium hydride. As the solvent, use can be made of an ether suchas tetrahydrofuran, 1,4-dioxane and diglyme, and an aprotic solvent suchas dimethylformamide and dimethyl sulfoxide. The reaction may be carriedout in the absence of a solvent. The reaction temperature is selectedfrom a range of about 50° C. to about 200° C.

In a case where X¹ is SO₂, an intermediate wherein the corresponding X¹is sulfur atom is oxidized by oxone (registered trade mark) orm-chloroperbenzoic acid (mCPBA).

In the process of preparing the compound (VIII) from the compound (I),the compound (V) can also be synthesized from the compound (II) by thesame method as above, or the compound (VIII) can also be obtained bysynthesizing the compound (V) from the compound (I) through the compound(IV) and converting the resultant to the compound (VII) which is thenconverted to the object.

Preparation Method 2

wherein L is a leaving group, R¹, Y¹, X¹ and Z¹ have the same meaningsas above, X is amino group, hydroxy group or mercapto group, and X³ is agroup shown by the following formula:

(wherein ring A, n, R, R², X², Y² and Y³ have the same meanings asabove), a leaving group, amino group, hydroxy group, mercapto group,carboxy group or sulfonic acid group.

The compound (XII) can be obtained by reacting the compound (XI) withthe compound (XIV) in the presence of a base.

As the base, use can be made of an alkali metal carbonate such as sodiumcarbonate and potassium carbonate, an alkaline earth metal carbonatesuch as calcium carbonate, a metal hydroxide such as sodium hydroxideand potassium hydroxide, an organic base such as triethylamine,diisopropylethylamine, pyridine and 4-dimethylaminopyridine, a metalalkoxide such as sodium methoxide. As the solvent, use can be made of ahalogenated hydrocarbon such as methylene chloride, an ether such asdiethyl ether, tetrahydrofuran and 1,4-dioxane, an alcohol such asmethanol and ethanol, and an aprotic solvent such as dimethylformamide,dimethyl sulfoxide and acetonitrile. The reaction temperature isselected from a range of about 0° C. to around the boiling point of thesolvent.

The compound (VIII) can be obtained by reacting the compound (XII) withthe compound (XV) in the presence or absence of a base.

As the base, use can be made of an inorganic base including an alkalimetal carbonate such as sodium carbonate and potassium carbonate, analkaline earth metal carbonate such as calcium carbonate, a metalhydroxide such as sodium hydroxide and potassium hydroxide, an organicbase such as triethylamine, diisopropylethylamine, pyridine and4-dimethylaminopyridine, a metal alkoxide such as sodium methoxide. Asthe solvent, use can be made of an ether such as tetrahydrofuran,1,4-dioxane and diglyme, an alcohol such as methanol and ethanol, and anaprotic solvent such as toluene, dimethylformamide and dimethylsulfoxide. The reaction may be carried out in the absent of a solvent.The reaction temperature is selected from a range of room temperature toaround the boiling point of the solvent.

In the process for preparing the compound (VIII) from the compound(XII), the compound (VIII) can also be obtained by synthesizing thecompound (XIII) and then reacting it with the compound (XVI).

In a case where X is amino group, the compound (XIII) can be obtained byreacting the compound (XII) with guanidine in the presence or absence ofa base.

As the base, use can be made of an alkali metal carbonate such as sodiumcarbonate and potassium carbonate, an alkaline earth metal carbonatesuch as calcium carbonate, a metal hydroxide such as sodium hydroxideand potassium hydroxide, an organic base such as triethylamine,diisopropylethylamine, pyridine and 4-dimethylaminopyridine, a metalalkoxide such as sodium methoxide.

As the solvent, use can be made of an ether such as tetrahydrofuran,1,4-dioxane and diglyme, an alcohol such as methanol and ethanol, and anaprotic solvent such as toluene, dimethylformamide and dimethylsulfoxide. The reaction may be carried out in the absence of a solvent.The reaction temperature is selected from a range of room temperature toaround the boiling point of the solvent.

In a case where X is hydroxy group, the compound (XIII) can be obtainedby reacting the compound (XII) with urea in the presence or absence of abase. As the base, use can be made of an alkali metal carbonate such assodium carbonate and potassium carbonate, an alkaline earth metalcarbonate such as calcium carbonate, a metal hydroxide such as sodiumhydroxide and potassium hydroxide, an organic base such astriethylamine, diisopropylethylamine, pyridine and4-dimethylaminopyridine, and a metal alkoxide such as sodium methoxide.

As the solvent, use can be made of an ether such as tetrahydrofuran,1,4-dioxane and diglyme, an alcohol such as methanol and ethanol, and anaprotic solvent such as toluene, dimethylformamide and dimethylsulfoxide. The reaction may be carried out in the absence of a solvent.The reaction temperature is selected from a range of room temperature toaround the boiling point of the solvent.

In a case where X is mercapto group, the compound (XIII) can be obtainedby reacting the compound (XII) with benzoylisothiocyanate in thepresence or absence of a base, followed by cyclization. In the reactionwith benzoylisothiocyanate, as the base, use can be made of an alkalimetal carbonate such as sodium carbonate and potassium carbonate, analkaline earth metal carbonate such as calcium carbonate and an organicbase such as triethylamine, diisopropylethylamine, pyridine and4-dimethylaminopyridine. As the solvent, use can be made of ahalogenated hydrocarbon such as methylene chloride, an ether such astetrahydrofuran and 1,4-dioxane and an aprotic solvent such asdimethylformamide and dimethyl sulfoxide. The reaction temperature isselected from a range of 0° C. to around the boiling point of thesolvent.

In the cyclization reaction, as the base, use can be made of an alkalimetal hydroxide such as sodium hydroxide and potassium hydroxide and ametal alkoxide such as sodium methoxide and potassium t-butoxide. As thesolvent, use can be made of an ether such as tetrahydrofuran, an alcoholsuch as ethanol and 2-propanol and an aprotic solvent such asdimethylformamide and dimethyl sulfoxide. The reaction temperature isselected from a range of around room temperature to around the boilingpoint of the solvent.

The compound (VIII) can be obtained by reacting the compound (XIII) withthe compound (XVI) in the presence of a base. As the base, use can bemade of an alkali metal carbonate such as sodium carbonate and potassiumcarbonate, an alkaline earth metal carbonate such as calcium carbonate,a metal hydroxide such as sodium hydroxide and potassium hydroxide, ametal hydrogenate such as sodium hydride, an organic base such astriethylamine, diisopropylethylamine, pyridine and4-dimethylaminopyridine and a metal alkoxide such as potassiumt-butoxide. As the solvent, use can be made of a halogenated hydrocarbonsuch as carbon tetrachloride, chloroform and methylene chloride, anether such as diethyl ether, tetrahydrofuran and 1,4-dioxane and anaprotic solvent such as dimethylformamide, dimethyl sulfoxide andacetonitrile. The reaction temperature is selected from a range of about0° C. to around the boiling point of the solvent.

Preparation Method 3

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above.

In a case where X³ is a leaving group, amino group, hydroxy group,mercapto group, carboxy group or sulfonic acid group in the aboveformula (II) to (XVI), each of them can be respectively converted to thecompound (XVIII) according to a method known to the skilled artisan orsimilar thereto. Those methods are, for example, disclosed in“Comprehensive Organic Transformations, R. C. Lalock (VCH Publishers,Inc. 1989)”. Those methods are concretely explained below.

(1) A case where X³ is a leaving group

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above, and X⁴ is oxygen atom, sulfur atom or NR⁵.

The compound (XX) can be obtained by reacting the compound (V) (whereinX³ is a leaving group) with the compound (XXI).

In case where X⁴ is NR⁵, the reaction is conducted in the presence orabsence of a base. As the base, use can be made of an alkali metalcarbonate such as sodium carbonate and potassium carbonate, an alkalineearth metal carbonate such as calcium carbonate, a metal hydroxide suchas sodium hydroxide and potassium hydroxide and an organic base such astriethylamine, diisopropylethylamine and 4-dimethylaminopyridine. As thesolvent, use can be made of an ether such as tetrahydrofuran and1,4-dioxane and diglyme, an alcohol such as propanol and butanol and anaprotic solvent such as dimethylformamide, dimethyl sulfoxide oracetonitrile. The reaction may also be carried out in the absence of asolvent. The reaction temperature is selected from a range of roomtemperature to around the boiling point of the solvent.

In case where X⁴ is oxygen atom or sulfur atom, the reaction isconducted in the presence of a base. As the base, use can be made of analkali metal such as sodium or potassium or a alkali metal hydride suchas sodium hydride. As the solvent, use can be made of an ether such astetrahydrofuran and 1,4-dioxane and diglyme and an aprotic solvent suchas dimethylformamide or dimethyl sulfoxide. The reaction may also becarried out in the absence of a solvent. The reaction temperature isselected from a range of room temperature to around the boiling point ofthe solvent.

(2) A Case where X³ is Amino Groupi) A case where X² is NR⁵CO, NR⁵SO₂, NR⁵CONR⁶ or NR⁵CSNR⁶

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above, X⁵ is COCl, SO₂Cl, NCO or NCS, and X⁶ is NR⁵CO,NR⁵SO₂, NR⁵CONR⁶ or NR⁵CSNR⁶.

The compound (XX) can be obtained by reacting the compound (V) (whereinX³ is amino group) with the compound (XXII) in the presence or absenceof a base. As the base, use can be made of an alkali metal carbonatesuch as sodium carbonate and potassium carbonate, an alkaline earthmetal carbonate such as calcium carbonate and an organic base such astriethylamine, diisopropylethylamine and 4-dimethylaminopyridine. As thesolvent, use can be made of a halogenated hydrocarbon such as carbontetrachloride, chloroform and methylene chloride, an ether such asdiethyl ether, tetrahydrofuran and 1,4-dioxane and an aprotic solventsuch as toluene and xylene. The reaction temperature is selected from arange of about 0° C. to around the boiling point of the solvent.

ii) A Case where X² is NR⁵

The compound (XIX-2) or the compound (XIX-3) which corresponds to thecompound of formula (1) can be obtained by the following process.

wherein ring A, n, R, R¹, R², R⁵, X¹, X², Y¹, Y², Y³, Z¹ and L have thesame meanings as above, and Y² is combined with methylene to representY².

The compound (XIX-2) can be obtained by reacting the compound (V) withthe aldehyde compound (XXII-2) using a reducing agent such as sodiumborohydride (NaBH₄) in a solvent such as methanol. When R⁵ is excepthydrogen atom, the compound (XIX-3) can be obtained by reacting thecompound (XIX-2) with alkylating reagent such as a halogenated alkylreagent in the presence of a base such as potassium carbonate in asolvent such as acetonitrile or dimethylformamide.

The compound (XIX-2) or the compound (XIX-3) can be also obtained in thefollowing process.

wherein ring A, n, R, R¹, R², R⁵, X¹, X², Y¹, Y², Y³, Z¹ and L have thesame meanings as above, and L′ and L″ is the same or different, and is aleaving group.

The compound (V-3) can be obtained by reacting the compound (IV) withthe compound shown as L″-Z¹-L′ such as alkylene dihalide in the presenceof a base such as potassium carbonate in the solvent such asdimethylformamide. The compound (XIX-2) can be obtained by reacting thecompound (V-3) with the compound (XXII-3) under the same condition. Thecompound (XIX-2) is converted to the compound (XIX-3) wherein R⁵ is thegroup except hydrogen in the same manner as mentioned above.

The compound (XIX-3) can be also obtained by the following process.

wherein ring A, n, R, R¹, R², R⁵, X¹, X², Y¹, Y², Y³, L′ and L″ have thesame meanings as above.

The compound (XXII-4) can be obtained by alkylating the compound(XXII-3) in the two-steps process. The compound (XIX-3) can be obtainedby condensing the compound (XXII-4) with the compound (IV) in thepresence of a base such as potassium carbonate in a solvent such asdimethylformamide. In the case of the compound (XIX-3) wherein R⁵represent hydrogen atom, the compound (XXII-4) can be obtained byreacting the compound (XXII-3) with the compound shown as L″-Z¹-L′ suchas alkylene dihalide.

The amino group in the compound (V) can be protected if necessary, andthe protecting group of the amino group can be deprotected to give thecompound (V) wherein X³ represents amino group. For example, thecompound (V-1) can be obtained by reacting the compound (IV) with thecompound (IX-2) in the presence of a base such as potassium carbonate ina solvent such as dimethylformamide. The obtained compound can betreated with hydrazine in a solvent such as ethanol to give the compound(V-2), namely the compound (V) wherein X³ represents amino group.

wherein R¹, X¹, Y¹, Z¹ and L have the same meanings as above.

(3) A Case where X³ is Carboxy Group or Sulfonic Acid Group

wherein ring A, n, R, R¹, R², R⁵, X¹, X², Y¹, Y², Y³ and Z¹ have thesame meanings as above, and X⁷ is CONR⁵ or SO₂NR⁵.

The compound (XX) can be obtained by converting the compound (V) whereinX³ is carboxy group or sulfonic acid group to an acid halide compoundand then reacting it with the compound (XXIII) in the presence orabsence of a base. As the halogenating agent, use can be made of thionylchloride, phosphoryl chloride, phosphorus pentachloride and phosphorustrichloride. As the solvent, use can be made of a halogenatedhydrocarbon such as carbon tetrachloride, chloroform and methylenechloride, an ether such as diethyl ether, tetrahydrofuran and1,4-dioxane and an aprotic solvent such as toluene and xylene. Thereaction temperature is selected from a range of about 0° C. to aroundthe boiling point of the solvent. As the base, use can be made of analkali metal carbonate such as sodium carbonate and potassium carbonate,an alkaline earth metal carbonate such as calcium carbonate and anorganic base such as triethylamine, diisopropylethylamine and4-dimethylaminopyridine.

Each step described in the preparation method 3 can be conducted withthe use of any of the compounds in the preparation method 1 or 2 as astarting material, so far as it does not hinder the preparation stepsafter the present preparation step, and can be conducted by any of thereaction scheme described in the preparation method 1 or 2. Further, inthe preparation method 3, the compound of the formula (XX) can beconverted to the compound of the formula (XIX) by the method describedin the preparation method 1.

Preparation Method 4

wherein L is a leaving group, and R¹, Y¹, X¹, Z¹ and X³ have the samemeanings as above.

The compound (XXV) can be obtained by reacting the compound (XXIV) withammonia in an aqueous solution, an organic solvent or a mixture of waterand an organic solvent.

The organic solvent includes an alcohol such as methanol, ethanol,propanol, and butanol, an ether such as tetrahydrofuran, 1,4-dioxane anddiglyme, an aprotic solvent such as acetonitrile. The reactiontemperature is selected from, for instance, around room temperature to200° C. A reaction vessel such as an autoclave may optionally be used inthe reaction.

The compound (XXVI) can be obtained in the same manner as the synthesisof the compound (III) using the compound (XXV).

The compound (XXVII) can be obtained by reacting the compound (XXVI)with sodium methoxide.

As the organic solvent, use is made of an ether such as diethyl ether,tetrahydrofuran and 1,4-dioxane, an aprotic solvent such asdimethylformamide and an alcohol such as methanol.

The reaction temperature is selected from, for instance, a range of roomtemperature to around the boiling point of the solvent.

Further, the compound (XXVII) can be obtained by treating the compound(XXVI) with an aqueous alkaline solution containing methanol.

As the aqueous alkaline solution, use is made of an aqueous solution ofan alkali metal hydroxide such as sodium hydroxide and potassiumhydroxide solution. The reaction temperature is selected from, forinstance, a range of room temperature to around the boiling point of thesolvent.

The compound (XXX) can be obtained in the same manner as the synthesisof the compound (VIII) using the compound (XXVII) in the preparationmethod 1.

Additionally, in the step from the compound (XXV) to the compound (XXX),the compound (XXVIII) is prepared by the same method as above, and it isconverted into the compound (XXIX). The compound (XXX) can also beobtained from the compound (XXIX).

The compound (XXXI) can be obtained by treating the compound (XXX) withtrifluoroacetic acid in the solvent such as methanol.

The compound (XXXII) can be prepared using the compound (XXXI) in thesame manner as the synthesis of the compound (II) from the compound (I),or the synthesis of the compound (V) from the compound (IV) in thepreparation method 1.

The compound (VIII) can be obtained by acid treatment of the compound(XXXII).

As the acid, use can be made of, for instance, an inorganic acid such ashydrochloric acid, hydrobromic acid and sulfuric acid, and an organicacid such as trifluoroacetic acid.

As the solvent, use can be made of, for instance, water, and a mixtureof water and an organic solvent. The organic solvent is exemplified byan ether such as diethyl ether and tetrahydrofuran, an aprotic solventsuch as dimethylformamide and acetonitrile and an alcohol such asmethanol and ethanol. The reaction temperature is selected from, forinstance, a range from room temperature to around the boiling point ofthe solvent.

The compound (XXXII) wherein X³ represents a leaving group, amino group,hydroxy group, mercapto group, carboxy group or sulfonic acid group canbe converted into the compound (XVIII-2):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above, by using a method described in the above mentionedpreparation method 3. And then, the compound (XVIII-2) is subjected todeprotection of the methoxy group by the acid treatment mentioned aboveto prepare the compound (XVIII):

wherein ring A, n, R, R¹, R², X¹, X², Y¹, Y², Y³ and Z¹ have the samemeanings as above.

The compound (XXXII) can also be subjected to deprotection of themethoxy group by the above mentioned acid treatment to give the8-oxo-compound (VIII), and then the compound (VIII) is converted intothe compound (XVIII) by using the preparation method 3.

In a case where the adenine compound of the present invention, itsintermediate or the starting compound contains a functional group, areaction for increasing a carbon atom, a reaction for introducing asubstituent or a reaction for conversion of the functional group can beconducted optionally according to a manner conventional to the skilledartisan in an appropriate step, namely in an intermittent step in eachof the preparation methods described in the preparation method 1 or 2.For this purpose, the methods described in “JIKKEN KAGAKU-KOZA (editedby NIHON KAGAKU-KAI, MARUZEN)”, or “Comprehensive OrganicTransformation, R. C. Lalock (VCH Publishers, Inc. 1989)” can be used.The reaction for increasing a carbon atom includes a method comprisingconverting an ester group to hydroxymethyl group using a reducing agentsuch as aluminum lithium hydride, introducing a leaving group and thenintroducing a cyano group. The reacting for conversion of a functionalgroup includes a reaction for conducting acylation or sulfonylationusing an acid halide, a sulfonyl halide, etc., a reaction for reactingan alkylation agent such as a halogenated alkyl, a hydrolysis reaction,a reaction for C—C bond formation such as Friedel-Crafts reaction andWittig reaction, and oxidation reaction, a reducing reaction, etc.

In a case where the compound of the present invention or itsintermediate contains a functional group such as amino group, carboxygroup, hydroxy group and oxo group, a technology of protection andde-protection can optionally be used. A preferable protecting group, aprotection method and a deprotection method are described in details in“Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons,Inc.; 1990)”, etc.

The compound (1) of the present invention and the intermediate compoundfor production thereof can be purified by a method known to the skilledartisan. For instance, purification can be conducted by columnchromatography (e.g. silica gel column chromatography or ion exchangechromatography) or recrystallization. As the recrystallization solvent,for instance, use can be made of an alcohol such as methanol, ethanoland 2-propanol, an ether such as diethyl ether, an ester such as ethylacetate, an aromatic hydrocarbon such as benzene and toluene, a ketonesuch as acetone, a hydrocarbon such as hexane, an aprotic solvent suchas dimethylformamide and acetonitrile, water and a mixture of two ormore thereof. As other purification method, use can be made of thosedescribed in “JIKKEN KAGAKU-KOZA (edited by NIHON KAGAKU-KAI, MARUZEN)Vol. 1”, etc.

In a case where the compound of the formula (1) of the present inventioncontains one or more asymmetric carbons, its production can be conductedby using the starting material containing those asymmetric carbons or byintroducing the asymmetric carbons during the production steps. Forinstance, in a case of an optical isomer, it can be obtained by using anoptically active starting material or by conducting an opticalresolution at a suitable stage of the production steps. The opticalresolution method can be conducted by a diastereomer method comprisingallowing the compound of the formula (1) or its intermediate to form asalt with an optically active acid (e.g. a monocarboxylic acid such asmandelic acid, N-benzyloxy alanine and lactic acid, a dicarboxylic acidsuch as tartaric acid, o-diisopropylidene tartrate and malic acid, asulfonic acid such as camphor sulfonic acid and bromocamphor sulfonicacid) in an inert solvent (e.g. an alcohol such as methanol, ethanol,and 2-propanol, an ether such as diethyl ether, an ester such as ethylacetate, a hydrocarbon such as toluene, an aprotic solvent such asacetonitrile and a mixture of two or more thereof).

In a case where the compound of the formula (1) or its intermediatecontains a functional group such as carboxylic group, the object can beattained also by forming a salt with an optically active amine (e.g. anorganic amine such as α-phenethylamine, quinine, quinidine,cinchonidine, cinchonine and strychinene).

The temperature for formation of the salt is selected from roomtemperature to the boiling point of the solvent. In order to increaseoptical purity, the temperature is preferably once increased up to theboiling point of the solvent. Upon recovering the salt formed byfiltration, the yield can be increased optionally by cooling. An amountof the optical active acid or amine is about 0.5 to about 2.0equivalent, preferably around 1 equivalent, relative to the substrate.An optically active salt with highly optical purity can be obtainedoptionally by recrystallization from an inert solvent (e.g. an alcoholsuch as methanol, ethanol and 2-propanol, an ether such as diethylether, an ester such as ethyl acetate, a hydrocarbon such as toluene, anaprotic solvent such as acetonitrile and a mixture of two or morethereof). If necessary, the optically resoluted salt can be convertedinto a free form by treating with an acid or a base by the conventionalmethod.

The 8-oxoadenine compound and its pharmaceutically acceptable salt ofthe present invention is useful as an immuno-modulator and thus usefulas a therapeutic and prophylactic agent for diseases associated with anabnormal immune response (e.g. autoimmune diseases and allergicdiseases) and various infections and cancers which are required foractivation of an immune response. For instance, the 8-oxoadeninecompound and its pharmaceutically acceptable salt is useful as atherapeutic and prophylactic agent for the diseases mentioned in thefollowing (1)-(8).

(1) Respiratory diseases: asthma, including bronchial, allergic,intrinsic, extrinsic, exercise-induced, drug-induced (including NSAIDsuch as aspirin and indomethacin) and dust-induced asthma; intermittentand persistent and of all severities, and other causes of airwayhyper-responsiveness; chronic obstructive pulmonary disease (COPD);bronchitis including infectious and eosinophilic bronchitis; emphysema;bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and relateddiseases; hypersensitivity pneumonitis; lung fibrosis includingcryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias,fibrosis complicating antineoplastic therapy and chronic infection,including tuberculosis and aspergillosis and other fungal infections;complications of lung transplantation; vasculitic and thromboticdisorders of the lung vasculature, and pulmonary hypertension;antitussive activity including treatment of chronic cough associatedwith inflammatory and secretory conditions of the airways, andiatrogenic cough; acute and chronic rhinitis including rhinitismedicamentosa, and vasomotor rhinitis; perennial and seasonal allergicrhinitis including rhinitis nervosa (hay fever); nasal polyposis; acuteviral infection including the common cold, and infection due torespiratory syncytial virus, influenza, coronavirus (including SARS) andadenovirus.

(2) (Skin) psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions.

(3) (Eyes) blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune; degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial.

(4) (Genitourinary) nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale).

(5) (Allograft rejection) acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease.

(6) Other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome,Sazary syndrome.

(7) (Oncology) treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumor recurrences, and paraneoplastic syndromes.

(8) (Infectious diseases) virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, HIV, CMV, VZV, rhinovirus, adenovirus,coronavirus, influenza, para-influenza; bacterial diseases such astuberculosis and mycobacterium avium, leprosy; other infectiousdiseases, such as fungal diseases, chlamydia, candida, aspergillus,cryptococcal meningitis, pneumocystis carnii, cryptosporidiosis,histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis.

The 8-oxoadenine compounds or pharmaceutically acceptable salt thereofcan also be used as vaccine adjuvant.

The 8-oxoadenine compound of the present invention, or itspharmaceutically acceptable salt shows an interferon inducing activityand/or a suppressing activity of the production of IL-4 and IL-5, andthus shows an effect as a medicament having an immunomodulating activityspecific against type 1 helper T-cell (Th1 cell)/type 2 helper T-cell(Th2 cell), namely, preferably useful as a prophylactic or therapeuticagent for asthma caused by Th2 cell, and allergic diseases such asallergic rhinitis, allergic conjunctivitis and atopic dermatosis.Additionally, due to its an immuno activating activity such asinterferon α and interferon γ inducing activity, it is useful as aprophylactic or therapeutic agent for cancer, a viral disease caused byinfection with virus such as hepatitis B virus, hepatitis C virus, HIVand human papilloma virus (HPV), infections by bacteria and dermatosissuch as psoriasis.

The compound of the present invention has no limitation as to itsadministration formulation and is administered orally or parenterally.The preparation for oral administration can be exemplified by capsules,powders, tablets, granules, fine-grain, syrups, solutions, suspensions,etc., and the preparation for parenteral administration can beexemplified by injections, drips, eye-drops, intrarectal preparations,inhalations, sprays (e.g. sprays, aerosols, liquids/suspensions forcartridge spray for inhalators or insufflators), lotions, gels,ointments, creams, transdermal preparations, transmucosa preparations,collunariums, ear drops, tapes, transdermal patches, cataplasms, powdersfor external application, and the like. Those preparations can beprepared by so-far known manners, and acceptable conventional carriers,fillers, binders, lubricants, stabilizers, disintegrants, bufferingagents, solubilizing agents, isotonic agents, surfactants, antiseptics,perfumes, and so on can be used. Two or more pharmaceutical carriers canbe appropriately used.

A liquid preparation such as emulsions and syrups, among thepreparations for oral administration, can be prepared by using additivesincluding water; a sugar such as sucrose, sorbitol and fructose; aglycol such as polyethylene glycol and propylene glycol; an oil such assesame oil, olive oil and soybean oil; an antiseptic such asp-hydroxybenzoic acid ester; a flavor such as strawberry flavor andpeppermint flavor. The solid preparation such as capsules, tablets,powders and granules can be prepared by using a filler such as lactose,glucose, sucrose and mannitol; a disintegrant such as starch and sodiumalginate; a lubricant such as magnesium stearate and talc; a binder suchas polyvinyl alcohol, hydroxypropyl cellulose and gelatin; a surfactantsuch as a fatty acid ester; a plasticizer such as glycerin.

The liquid preparation such as injections, drips, eye-drops and eardrops, among the preparations for parenteral administration, can beprepared preferably as a sterilized isotonic liquid preparation. Forinstance, injections can be prepared by using an aqueous medium such asa salt solution, a glucose solution or a mixture of a salt solution anda glucose solution. The preparation for intrarectal administration canbe prepared by using a carrier such as cacao butter usually in the formof suppository.

The ointments, creams and gels contain the compound of the presentinvention usually in an amount of 0.01-10 w/w %, and there may beincorporated a thickening agent suitable to an aqueous or oily baseand/or a gelling agent and/or a solvent. The base is exemplified bywater and/or oil such as liquid paraffin, a vegetable oil such asarachis oil and castor oil, a solvent such as polyethylene glycol, andso on. The thickening agent and gelling agent are exemplified by softparaffin, aluminum stearate, cetostearic alcohol, polyethylene glycol,sheep fat, beeswax, carboxypolymethylene and cellulose derivativesand/or glyceryl monostearate and/or nonionic emulsifiers.

The lotions contain the compound of the present invention usually in anamount of 0.01-10 w/w %, and it may be prepared with the use of anaqueous or oily base, it may contain generally emulsifiers, stabilizers,dispersing agents, precipitation inhibitors and also thickening agents.

Powders for external use contain the compound of the present inventionusually an amount of 0.01-10 w/w %, and it may be formulated using asuitable powdery base such as talc, lactose and starch.

The drips may be formulated by using an aqueous or non-aqueous base, andmay contain dispersing agents, solubilizing agents, precipitationinhibitors or antiseptics.

The sprays may be formulated into an aqueous solution or suspensionusing a suitable liquid propellant, or into an aerosol distributed froma pressured package such as a metered-dose inhaler.

The aerosols suitable to inhalation may be a suspension or aqueoussolution, and they contain generally the compound of the presentinvention and a suitable propellant such as fluorocarbon,hydrogen-containing chlorofluorocarbon and a mixture thereof,particularly hydrofluoroalkane, specifically 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosolsmay contain optionally additional excipients well known in the art suchas a surfactant, (e.g., oleic acid or lecitin) and a co-solvent such asethanol.

The gelatin capsules or cartridges used for inhalator or insufflator maybe formulated by using a powdery mixture of the compounds used in thepresent invention and a powdery base such as lactose and starch. Theycontain the compound of the present invention usually in an amount of 20μg-10 mg. The compound of the present invention may be administeredwithout using excipients such as lactose as an alternative method.

The 8-oxoadenine compound of the present invention is preferablyparenterally administered as a preparation for topical administration.The suitable preparation is exemplified by ointments, lotions, creams,gels, tapes, transdermal patches, cataplasms, sprays, aerosols, aqueoussolutions/suspensions for cartridge spray for inhalators orinsufflators, eye-drops, ear drops, nasal drops, powders for externaladministrations and so on.

A ratio of the active compound of the present invention in thepreparation for topical administration of the present invention is,though depending upon the formulation, generally 0.001-10 wt %,preferably 0.005-1%. The ratio used in powders for inhalation orinsufflation is 0.1-5%.

In a case of aerosols, the compound of the present invention ispreferably contained in an amount of 20-2000 μg, more preferably about20 μg-500 μg per each a measured amount or one sprayed amount. Thedosage is once or several times per day, for instance, 2, 3, 4 or 8times, and one to three units are administered per each time.

The 8-oxoadenine compound of the present invention, preferably thecompound (I) wherein R² is except hydrogen atom, its tautomer or itspharmaceutically acceptable salt can show the pharmaceutical activity atthe site administered in a case of topical administration, and furtherthey are useful as a pharmaceutical preparation for topicaladministration characterized by showing no systemic pharmacologicalactivity because the compounds are converted by an enzyme in vivo intodifferent compounds (degraded compounds) having only a substantiallyreduced medical effect. The medical effect used here means apharmacological activity of the compound, including specifically aninterferon inducing activity, and a suppressing activity of theproduction IL-4 and/or IL-5.

The medical effect of the degraded compound is preferably 10 times, morepreferably 100 times, still more preferably 1000 times reduced comparingwith that of the parent compound.

The pharmacological activity can be measured by any of conventionalevaluation methods, preferably by an in vitro evaluation method.Specific examples of the methods are one described in Method inENZYMOLOGY (Academic Press), a method using commercially available ELISAkits (e.g. AN'ALYSA (immunoassay System)) and a method described inexamples of the present specification.

For instance, by measuring interferon inducing activity with bioassayusing cells of mouse spleen, the amount of each interferon induction(IU/ml at the same concentration of the parent compound (the compound ofthe present invention) and the degraded compound can be compared.

As the pharmacological activity, the activity in vivo caused byinterferon inducing activity, etc. is illustrated. Said activity in vivoincludes immune activating activity, influenza-like symptom, etc. Theimmune activating activity includes induction of cytotoxic activity suchas natural killer (NK) cells, etc. The influenza-like symptom includesfever, etc. The fever means elevation in body temperature of amammalian, for example, in a case of human, the fever means that thebody temperature increases more than normal temperature.

The topical administration is not limited as to the administrationmethod, and the administration is conducted in a case of administrationvia nasal cavity, alveolus or air way, by aeration or inhalation, in acase of administration to skin, by spreading on the skins, and in a caseof administration to eye, by eye dropping, etc. Preferableadministration is aeration and inhalation.

It can be confirmed that when the pharmaceutical composition for topicaladministration of the present invention is administered topically, thecompound of the present invention therein is converted to a degradedcompound in the blood, etc. in human or animal for example, by its halflife in the serum or in lever S9 in vitro. The test method to determinethe half life of the compound of the present invention in vitro isknown.

In the vitro measuring test, the compound of the present invention ismetabolized in liver S9 and its half life is preferably not longer than60 minutes, more preferably not longer than 30 minutes, and still morepreferably not longer than 10 minutes.

Further, the compound of the present invention is metabolized in serum,and its half life is preferably not longer than 60 minutes, morepreferably not longer than 30 minutes, and still more preferably notlonger than 10 minutes.

As the degraded compound, the compound of the formula (1) wherein R² isa hydrogen atom is exemplified, when the parent compound is the compoundof the formula (1) wherein R² is a group except hydrogen atom.

The method for measuring the half life in liver S9 is as follows.Namely, the compound of the present invention is added to a liver S9solution and incubated at 37±0.5° C. for 5 minutes to 2 hours. Byquantitative analyzing at the definite interval the amount of thecompound of the present invention remaining in the lever S9 solutionwith HPLC (high performance liquid chromatography), etc., the constantof quenching velocity calculated and the half life is calculated. Thespecific method is described in the Example.

The liver S9 solution used here means product obtained by homogenizing aliver of a mammal in an aqueous solution such as a physiological salinesolution, a sucrose solution and a KCl solution and then by recoveringthe supernatant upon centrifugation at 9000×g. The aqueous solution isused usually in an amount of 2 to 4 times as much as the liver. Themammal includes human, dog, rabbit, guinea pig, mouse and rat. The liverS9 can be used optionally after dilution with a buffering solution.

The measuring method for the half life in serum of the present inventionis as follows. Namely, the compound of the present invention is a serumsolution and incubated at 37±0.5° C. for 5 minutes to 2 hours. Byquantitative analyzing at the definite interval the amount of thecompound of the present invention remaining in the serum solution withHPLC (high performance liquid chromatograph), etc., the constant ofquenching velocity calculated and the half life is calculated.

The serum used here means a supernatant fraction obtained by leavinghemocytes and blood coagulation factor from blood by centrifugation,etc. and it may be used after dilution with a buffering solution.

The invention further relates to combination therapies wherein acompound of formula (1) or a pharmaceutically acceptable salt or apharmaceutical composition or formulation comprising a compound offormula (1) is administered concurrently or sequentially or as acombined preparation with another therapeutic agent or agents, for thetreatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases, COPD,asthma and allergic rhinitis, the compounds of the invention may becombined with agents such as tumour necrosis factor alpha (TNF-α)inhibitors such as anti-TNF monoclonal antibodies (for example Remicade,CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (suchas Enbrel); non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitorswhether applied topically or systemically (such as piroxicam,diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen,ketoprofen and ibuprofen, fenamates such as mefenamic acid,indomethacin, sulindac, azapropazone, pyrazolones such asphenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such asmeloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib andetoricoxib); glucocortico steroids (whether administered by topical,oral, intramuscular, intravenous, or intra-articular routes);methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofinor other parenteral or oral gold preparations.

The present invention still further relates to combination therapies ofa compound of the invention together with a leukotriene biosynthesisinhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activatingprotein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton;tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylphenolhydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compoundSB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such asL-739,010; 2-cyanoquinoline compounds such as L-746,530; indole andquinoline compounds such as MK-591, MK-886, and BAY x 1005.

The present invention still further relates to combination therapies ofa compound of the invention together with a receptor antagonist forleukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the groupconsisting of phenothiazin compound such as L-651,392; amidino compoundssuch as CGS-25019; benzoxalamines such as ontazolast;benzenecarboximidamides such as BIIL 284/260; and compounds such aszafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679),RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to combination therapies ofa compound of the invention together with a phosphodiesterase (PDE)inhibitor such as the methylxanthanines including theophylline andaminophylline; and selective PDE isoenzyme inhibitors including PDE4inhibitors and inhibitors of isoform PDE4D, and inhibitors of PDE5.

The present invention still further relates to combination therapies ofa compound of the invention together with histamine type 1 receptorantagonists such as cetirizine, loratadine, desloratadine, fexofenadine,acrivastine, terfenadine, astemizole, azelastine, levocabastine,chlorpheniramine, promethazine, cyclizine, and mizolastine, which isapplied orally, topically or parenterally.

The present invention still further relates to combination therapies ofa compound of the invention together with a gastroprotective histaminetype 2 receptor antagonist.

The present invention still further relates to combination therapies ofa compound of the invention with antagonists of the histamine type 4receptor.

The present invention still further relates to combination therapies ofa compound of the invention together with an alpha-1/alpha-2adrenoceptor agonist, vasoconstrictor sympathomimetic agent, such aspropylhexedrine, phenylephrine, phenylpropanolamine, ephedrine,pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride,tetrahydrozoline hydrochloride, xylometazoline hydrochloride,tramazoline hydrochloride, and ethylnorepinephrine hydrochloride.

The present invention still further relates to combination therapies ofa compound of the invention together with anticholinergic agentsincluding muscarinic receptor (M1, M2 and M3) antagonists such asatropine, hyoscine, glycopyrrolate, ipratropium bromide; tiotropiumbromide; oxitropium bromide; pirenzepine; and telenzepine.

The present invention still further relates to combination therapies ofa compound of the invention together with a beta-adrenoceptor agonist(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,and pirbuterol.

The present invention still further relates to combination therapies ofa compound of the invention together with a chromone, including sodiumcromoglycate and nedocromil sodium.

The present invention still further relates to combination therapies ofa compound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to combination therapies ofa compound of the invention together with an inhaled glucocorticoid,such as flunisolide, triamcinolone acetonide, beclomethasonedipropionate, budesonide, fluticasone propionate, ciclesonide, andmometasone furoate.

The present invention still further relates to combination therapies ofa compound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., stromelysin, collagenase, gelatinase,aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8),collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10),stromelysin-3 (MMP-11), MMP-9 and MMP-12.

The present invention still further relates to combination therapies ofa compound of the invention together with modulators of chemokinereceptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3,CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—Cfamily); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) andCX3CR1 (for the C—X3-C family).

The present invention still further relates to combination therapies ofa compound of the invention together with a cytokine or a modulator ofcytokine function including agents which act on cytokine signallingpathways, such as alpha-, beta-, and gamma-interferon; interleukins (IL)including IL1 to 15, and interleukin antagonists or inhibitors.

The present invention still further relates to combination therapies ofa compound of the invention together with an immunoglobulin (Ig), an Igpreparation, or an antagonist or antibody modulating Ig function such asanti-IgE (omalizumab).

The present invention still further relates to combination therapies ofa compound of the invention together with thalidomide and derivatives,or systemic or topically-applied anti-inflammatory agents such asretinoids, dithranol, and calcipotriol.

The present invention still further relates to combination therapies ofa compound of the invention together with an antibacterial agentincluding penicillin derivatives, tetracyclines, macrolides,beta-lactams, fluoroquinolones, and inhaled aminoglycosides; andantiviral agents including acyclovir, famciclovir, valaciclovir,ganciclovir, cidofovir, amantadine, rimantadine, ribavirin; zanamavirandoseltamavir; protease inhibitors such as indinavir, nelfinavir,ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitorssuch as didanosine, lamivudine, stavudine, zalcitabine and zidovudine;non-nucleoside reverse transcriptase inhibitors such as nevirapine andefavirenz.

The present invention still further relates to combination therapies ofa compound of the invention together with agents used for treatment ofcancer. Suitable agents to be used in the combination therapies include:

(i) antiproliferative/antineoplastic drugs and combinations thereof,which are used as an anticancer agent, such as alkylating agents (forexample cis platin, carboplatin, cyclophosphamide, nitrogen mustard,melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites(for example fluoropyrimidines like 5-fluorouracil and tegafur,antifolates such as raltitrexed, methotrexate, cytosine arabinoside,hydroxyurea, gemcitabine and paclitaxel; antitumour antibiotics (forexample anthracyclines like adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vinca alkaloids likevincristine, vinblastine, vindesine and vinorelbine and taxoids liketaxol and taxotere); and topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine, topotecanand camptothecins);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti erbb2 antibody trastuzumab and the anti erbb1 antibodycetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinaseinhibitors and serine/threonine kinase inhibitors, for exampleinhibitors of the epidermal growth factor family (for example EGFRfamily tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxy-ethoxy)quinazolin-4-amine(erlotinib, OSI 774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti vascularendothelial cell growth factor antibody bevacizumab, compounds disclosedin WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compoundsthat work by other mechanisms (for example linomide, inhibitors ofintegrin αvβ3 function and angiostatin);(vi) vascular damaging agents such as combretastatin A4 and compoundsdisclosed in WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, WO02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene directed enzyme pro drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex vivo and in vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte macrophage colony stimulating factor, approaches to decreaseT cell anergy, approaches using transfected immune cells such ascytokine transfected dendritic cells, approaches using cytokinetransfected tumour cell lines and approaches using anti idiotypicantibodies.

The compounds of the present invention are illustrated in the followingTables 1 to 29, but should not be limited to these compounds. In theseTables, the compounds of the present invention are shown in a form of8-hydroxy type for convenience and it is not different from 8-oxo type.

TABLE 1

—L¹— —(CH₂)₃O— —(CH₂)₄O— —(CH₂)₂OCH₂— —(CH₂)₂O(CH₂)₂— —(CH₂)₃OCH₂——(CH₂)₂S— —(CH₂)₃S— —(CH₂)₄S— —(CH₂)₂SCH₂— —(CH₂)₂S(CH₂)₂— —(CH₂)₃SCH₂——(CH₂)₂SO₂— —(CH₂)₃SO₂— —(CH₂)₂NH— —(CH₂)₃NH— —(CH₂)₄NH— —(CH₂)₂NHCH₂——(CH₂)₂NH(CH₂)₂— —(CH₂)₃NHCH₂— —(CH₂)₂N(CH₃)— —(CH₂)₃N(CH₃)——(CH₂)₄N(CH₃)— —(CH₂)₂N(CH₃)CH₂— —(CH₂)₃N(CH₃)CH₂— —(CH₂)₂NHCO——(CH₂)₃NHCO— —(CH₂)₂NHSO₂(CH₂)₂— —(CH₂)₃NHSO₂CH₂— —(CH₂)₂NCH₃SO₂CH₂——(CH₂)₂NHCONH— —(CH₂)₃NHCONH— —(CH₂)₂NHCSNH— —(CH₂)₃NHCSNH——(CH₂)₄NHCSNH— —CH₂CO— —(CH₂)₂CO— —(CH₂)₃CO— —(CH₂)₄CO— —CH₂COCH₂—

TABLE 2

—L¹— —(CH₂)₄SO₂— —(CH₂)₂SO₂CH₂— —(CH₂)₂SO₂(CH₂)₂— —(CH₂)₃SO₂CH₂——(CH₂)₂SO₂NH— —(CH₂)₃SO₂NH— —(CH₂)₄SO₂NH— —(CH₂)₂SO₂NHCH₂——(CH₂)₂SO₂NH(CH₂)₂— —(CH₂)₃SO₂NHCH₂— —(CH₂)₂SO₂N(CH₃)— —(CH₂)₃SO₂N(CH₃)——(CH₂)₂SO₂N(CH₃)CH₂— —(CH₂)₃SO₂N(CH₃)CH₂— —(CH₂)₄NHCO— —(CH₂)₂NHCOCH₂——(CH₂)₃NHCOCH₂— —(CH₂)₂N(CH₃)CO— —(CH₂)₃N(CH₃)CO— —(CH₂)₄N(CH₃)CO——(CH₂)₃N(CH₃)COCH₂— —(CH₂)₂NHCO₂CH₂— —(CH₂)₂NHSO₂— —(CH₂)₃NHSO₂——(CH₂)₂N(CH₃)SO₂— —(CH₂)₃N(CH₃)SO₂— —(CH₂)₄N(CH₃)SO₂— —(CH₂)₂NHSO₂CH₂——CH₂CO(CH₂)₂— —(CH₂)₂COCH₂— —(CH₂)₂CO(CH₂)₂— —CH₂CONH— —(CH₂)₂CONH——(CH₂)₃CONH— —CH₂CONHCH₂— —(CH₂)₂CONHCH₂— —CH₂CON(CH₃)— —(CH₂)₂CON(CH₃)——(CH₂)₃CON(CH₃)— —CH₂CON(CH₃)CH₂— —CH₂CON(CH₃)(CH₂)₂——(CH₂)₂CON(CH₃)CH₂—

TABLE 3

—L¹— —(CH₂)₂O— —(CH₂)₃O— —(CH₂)₄O— —(CH₂)₂OCH₂— —(CH₂)₂O(CH₂)₂——(CH₂)₃OCH₂— —(CH₂)₂S— —(CH₂)₃S— —(CH₂)₄S— —(CH₂)₂SCH₂— —(CH₂)₂S(CH₂)₂——(CH₂)₃SCH₂— —(CH₂)₂SO₂— —(CH₂)₂NH— —(CH₂)₃NH— —(CH₂)₄NH— —(CH₂)₂NHCH₂——(CH₂)₂NH(CH₂)₂— —(CH₂)₃NHCH₂— —(CH₂)₂N(CH₃)— —(CH₂)₃N(CH₃)——(CH₂)₄N(CH₃)— —(CH₂)₂N(CH₃)CH₂— —(CH₂)₃N(CH₃)CH₂— —(CH₂)₂NHCO——(CH₂)₃NHCO— —(CH₂)₄N(CH₃)SO₂— —(CH₂)₂N(CH₃)SO₂CH₂— —(CH₂)₂NHCONH——(CH₂)₃NHCONH— —(CH₂)₂NHCSNH— —(CH₂)₃NHCSNH— —(CH₂)₄NHCSNH— —CH₂CO——(CH₂)₂CO— —(CH₂)₃CO— —(CH₂)₄CO— —CH₂COCH₂— —CH₂CO(CH₂)₂—

TABLE 4

—L¹— —(CH₂)₃SO₂— —(CH₂)₄SO₂— —(CH₂)₂SO₂CH₂— —(CH₂)₂SO₂(CH₂)₂——(CH₂)₃SO₂CH₂— —(CH₂)₂SO₂NH— —(CH₂)₃SO₂NH— —(CH₂)₄SO₂NH——(CH₂)₂SO₂NHCH₂— —(CH₂)₂SO₂NH(CH₂)₂— —(CH₂)₃SO₂NHCH₂— —(CH₂)₂SO₂N(CH₃)——(CH₂)₃SO₂N(CH₃)— —(CH₂)₄SO₂N(CH₃)— —(CH₂)₂SO₂N(CH₃)CH₂——(CH₂)₃SO₂N(CH₃)CH₂— —(CH₂)₄NHCO— —(CH₂)₂NHCOCH₂— —(CH₂)₃NHCOCH₂——(CH₂)₂N(CH₃)CO— —(CH₂)₃N(CH₃)CO— —(CH₂)₄N(CH₃)CO— —(CH₂)₃N(CH₃)COCH₂——(CH₂)₂NHCO₂CH₂— —(CH₂)₂NHSO₂— —(CH₂)₃NHSO₂— —(CH₂)₄NHSO₂——(CH₂)₂NHSO₂CH₂— —(CH₂)₂NHSO₂(CH₂)₂— —(CH₂)₃NHSO₂CH₂— —(CH₂)₂N(CH₃)SO₂——(CH₂)₃N(CH₃)SO₂— —(CH₂)₂COCH₂— —CH₂CONH— —(CH₂)₂CONH— —(CH₂)₃CONH——CH₂CONHCH₂— —(CH₂)₂CONHCH₂— —CH₂CON(CH₃)— —(CH₂)₂CON(CH₃)——(CH₂)₃CON(CH₃)— —CH₂CON(CH₃)CH₂— —CH₂CON(CH₃)(CH₂)₂——(CH₂)₂CON(CH₃)CH₂—

TABLE 5

—R¹⁰ —O(CH₂)₂CH₃ —O(CH₂)₄CH₃ —O(CH₂)₂OH —O(CH₂)₃OH —O(CH₂)₂OCH₃—O(CH₂)₂OCH₂CH₃ —O(CH₂)₃OCH₃ —O(CH₂)₃CF₃

—S(CH₂)₂CH₃ —S(CH₂)₃CH₃ —S(CH₂)₂OH —S(CH₂)₃OH —S(CH₂)₄OH —S(CH₂)₂OCH₃—S(CH₂)₂OCH₂CH₃ —S(CH₂)₃OCH₃ —(CH₂)₃CH₃ —(CH₂)₂CO₂CH₃ —NH(CH₂)₂CH₃—NH(CH₂)₃CH₃ —NH(CH₂)₂OCH₃ —NH(CH₂)₃OCH₃ —NCH₃(CH₂)₂CH₃ —NCH₃(CH₂)₃CH₃—NCH₃(CH₂)₂OCH₃ —NCH₃(CH₂)₃OCH₃

TABLE 6

—R¹⁰ —O(CH₂)₂CH₃ —O(CH₂)₄CH₃ —O(CH₂)₂OH —O(CH₂)₃OH —O(CH₂)₂OCH₃—O(CH₂)₂OCH₂CH₃ —O(CH₂)₃OCH₃ —O(CH₂)₃CF₃

—S(CH₂)₂CH₃ —S(CH₂)₃CH₃ —S(CH₂)₂OH —S(CH₂)₃OH —S(CH₂)₄OH —S(CH₂)₂OCH₃—S(CH₂)₂OCH₂CH₃ —S(CH₂)₃OCH₃ —(CH₂)₃CH₃ —(CH₂)₂CO₂CH₃ —NH(CH₂)₂CH₃—NH(CH₂)₃CH₃ —NH(CH₂)₂OCH₃ —NH(CH₂)₃OCH₃ —NCH₃(CH₂)₂CH₃ —NCH₃(CH₂)₃CH₃—NCH₃(CH₂)₂OCH₃ —NCH₃(CH₂)₃OCH₃

TABLE 7

—R¹⁰ —O(CH₂)₂CH₃ —O(CH₂)₃CH₃ —O(CH₂)₂OH —O(CH₂)₃OH —O(CH₂)₂OCH₃—O(CH₂)₂OCH₂CH₃ —O(CH₂)₃OCH₃ —O(CH₂)₃CF₃

—S(CH₂)₂CH₃ —S(CH₂)₃CH₃ —S(CH₂)₂OH —S(CH₂)₃OH —S(CH₂)₄OH —S(CH₂)₂OCH₃—S(CH₂)₂OCH₂CH₃ —S(CH₂)₃OCH₃ —(CH₂)₃CH₃ —(CH₂)₂CO₂CH₃ —NH(CH₂)₂CH₃—NH(CH₂)₃CH₃ —NH(CH₂)₂OCH₃ —NH(CH₂)₃OCH₃ —NCH₃(CH₂)₂CH₃ —NCH₃(CH₂)₃CH₃—NCH₃(CH₂)₂OCH₃ —NCH₃(CH₂)₃OCH₃

TABLE 8

—R¹⁰ —O(CH₂)₂CH₃ —O(CH₂)₃CH₃ —O(CH₂)₂OH —O(CH₂)₃OH —O(CH₂)₂OCH₃—O(CH₂)₂OCH₂CH₃ —O(CH₂)₃OCH₃ —O(CH₂)₃CF₃

—S(CH₂)₂CH₃ —S(CH₂)₃CH₃ —S(CH₂)₂OH —S(CH₂)₃OH —S(CH₂)₄OH —S(CH₂)₂OCH₃—S(CH₂)₂OCH₂CH₃ —S(CH₂)₃OCH₃ —(CH₂)₃CH₃ —(CH₂)₂CO₂CH₃ —NH(CH₂)₂CH₃—NH(CH₂)₃CH₃ —NH(CH₂)₂OCH₃ —NH(CH₂)₃OCH₃ —NCH₃(CH₂)₂CH₃ —NCH₃(CH₂)₃CH₃—NCH₃(CH₂)₂OCH₃ —NCH₃(CH₂)₃OCH₃

TABLE 9

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃O— —S(CH₂)₃CH₃ —(CH₂)₄O— —S(CH₂)₂OH—(CH₂)₂OCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃OCH₂— —O(CH₂)₃CF₃ —(CH₂)₂S——S(CH₂)₂OCH₃ —(CH₂)₃S— —NH(CH₂)₂OCH₃ —(CH₂)₄S— —NCH₃(CH₂)₂OCH₃—(CH₂)₂SCH₂— —O(CH₂)₃OH —(CH₂)₂S(CH₂)₂— —S(CH₂)₃CF₃ —(CH₂)₃SCH₂—

—(CH₂)₂O(CH₂)₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂SO₂—

TABLE 10

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃SO₂— —S(CH₂)₃CH₃ —(CH₂)₄SO₂— —S(CH₂)₂OH—(CH₂)₂SO₂CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃SO₂CH₂— —O(CH₂)₃CF₃ —(CH₂)₂SO₂NH——S(CH₂)₂OCH₃ —(CH₂)₃SO₂NH— —NH(CH₂)₂OCH₃ —(CH₂)₄SO₂NH— —NCH₃(CH₂)₂OCH₃—(CH₂)₂SO₂NHCH₂— —O(CH₂)₃OH —(CH₂)₂SO₂NH(CH₂)₂— —S(CH₂)₃CF₃—(CH₂)₃SO₂NHCH₂—

—(CH₂)₂SO₂(CH₂)₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂SO₂NCH₃—

TABLE 11

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃SO₂NCH₃— —S(CH₂)₃CH₃ —(CH₂)₄SO₂NCH₃——S(CH₂)₂OH —(CH₂)₂SO₂NCH₃CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂NH— —O(CH₂)₃CF₃—(CH₂)₃NH— —S(CH₂)₂OCH₃ —(CH₂)₄NH— —NH(CH₂)₂OCH₃ —(CH₂)₂NHCH₂——NCH₃(CH₂)₂OCH₃ —(CH₂)₂NH(CH₂)₂— —O(CH₂)₃OH —(CH₂)₃NHCH₂— —S(CH₂)₃CF₃—(CH₂)₂NCH₃—

—(CH₂)₃SO₂NHCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NCH₃—

TABLE 12

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₄NCH₃— —S(CH₂)₃CH₃ —(CH₂)₂N(CH₃)CH₂——S(CH₂)₂OH —(CH₂)₃N(CH₃)CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NHCO— —O(CH₂)₃CF₃—(CH₂)₄NHCO— —S(CH₂)₂OCH₃ —(CH₂)₂NHCOCH₂— —NH(CH₂)₂OCH₃ —(CH₂)₃NHCOCH₂——NCH₃(CH₂)₂OCH₃ —(CH₂)₂N(CH₃)CO— —O(CH₂)₃OH —(CH₂)₃N(CH₃)CO— —S(CH₂)₃CF₃—(CH₂)₄N(CH₃)CO—

—(CH₂)₂NHCO— —(CH₂)₂CO₂CH₃ —(CH₂)₃N(CH₃)COCH₂—

TABLE 13

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂NCOOCH₂— —S(CH₂)₃CH₃ —(CH₂)₂NHSO₂——S(CH₂)₂OH —(CH₂)₃NHSO₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂NHSO₂(CH₂)₂— —O(CH₂)₃CF₃—(CH₂)₂NHSO₂CH₂— —S(CH₂)₂OCH₃ —(CH₂)₂N(CH₃)SO₂— —NH(CH₂)₂OCH₃—(CH₂)₃N(CH₃)SO₂— —NCH₃(CH₂)₂OCH₃ —(CH₂)₄N(CH₃)SO₂— —O(CH₂)₃OH—(CH₂)₂N(CH₃)SO₂CH₂— —S(CH₂)₃CF₃ —(CH₂)₂NHCONH—

—(CH₂)₂NHSO₂CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NHCONH—

TABLE 14

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂NHCSNH— —S(CH₂)₃CH₃ —(CH₂)₃NHCSNH——S(CH₂)₂OH —(CH₂)₄NHCSNH— —(CH₂)₂CO₂CH₃ —(CH₂)₂CO— —O(CH₂)₃CF₃—(CH₂)₃CO— —S(CH₂)₂OCH₃ —(CH₂)₄CO— —NH(CH₂)₂OCH₃ —CH₂COCH₂——NCH₃(CH₂)₂OCH₃ —CH₂CO(CH₂)₂— —O(CH₂)₃OH —(CH₂)₂COCH₂— —S(CH₂)₃CF₃—(CH₂)₂CO(CH₂)₂—

—CH₂CO— —(CH₂)₂CO₂CH₃ —CH₂CONH—

TABLE 15

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂CONH— —S(CH₂)₃CH₃ —(CH₂)₃CONH— —S(CH₂)₂OH—CH₂CONHCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂CONHCH₂— —O(CH₂)₃CF₃ —CH₂CON(CH₃)——S(CH₂)₂OCH₃ —(CH₂)₂CON(CH₃)— —NH(CH₂)₂OCH₃ —(CH₂)₃CON(CH₃)——NCH₃(CH₂)₂OCH₃ —CH₂CON(CH₃)CH₂— —O(CH₂)₃OH —CH₂CON(CH₃)(CH₂)₂——S(CH₂)₃CF₃ —(CH₂)₂CON(CH₃)CH₂—

—(CH₂)₃CONH—

TABLE 16

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃O— —S(CH₂)₃CH₃ —(CH₂)₄O— —S(CH₂)₂OH—(CH₂)₂OCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃OCH₂— —O(CH₂)₃CF₃ —(CH₂)₂S——S(CH₂)₂OCH₃ —(CH₂)₃S— —NH(CH₂)₂OCH₃ —(CH₂)₄S— —NCH₃(CH₂)₂OCH₃—(CH₂)₂SCH₂— —O(CH₂)₃OH —(CH₂)₂S(CH₂)₂— —S(CH₂)₃CF₃ —(CH₂)₃SCH₂—

—(CH₂)₂O(CH₂)₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂SO₂—

TABLE 17

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃SO₂— —S(CH₂)₃CH₃ —(CH₂)₄SO₂— —S(CH₂)₂OH—(CH₂)₂SO₂CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃SO₂CH₂— —O(CH₂)₃CF₃ —(CH₂)₂SO₂NH——S(CH₂)₂OCH₃ —(CH₂)₃SO₂NH— —NH(CH₂)₂OCH₃ —(CH₂)₄SO₂NH— —NCH₃(CH₂)₂OCH₃—(CH₂)₂SO₂NHCH₂— —O(CH₂)₃OH —(CH₂)₂SO₂NH(CH₂)₂— —S(CH₂)₃CF₃—(CH₂)₃SO₂NHCH₂—

—(CH₂)₂SO₂(CH₂)₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂SO₂NCH₃—

TABLE 18

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₃SO₂NCH₃— —S(CH₂)₃CH₃ —(CH₂)₄SO₂NCH₃——S(CH₂)₂OH —(CH₂)₂SO₂NCH₃CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂NH— —O(CH₂)₃CF₃—(CH₂)₃NH— —S(CH₂)₂OCH₃ —(CH₂)₄NH— —NH(CH₂)₂OCH₃ —(CH₂)₂NHCH₂——NCH₃(CH₂)₂OCH₃ —(CH₂)₂NH(CH₂)₂— —O(CH₂)₃OH —(CH₂)₃NHCH₂— —S(CH₂)₃CF₃—(CH₂)₂NCH₃—

—(CH₂)₃SO₂NHCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NCH₃—

TABLE 19

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₄NCH₃— —S(CH₂)₃CH₃ —(CH₂)₂N(CH₃)CH₂——S(CH₂)₂OH —(CH₂)₃N(CH₃)CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NHCO— —O(CH₂)₃CF₃—(CH₂)₄NHCO— —S(CH₂)₂OCH₃ —(CH₂)₂NHCOCH₂— —NH(CH₂)₂OCH₃ —(CH₂)₃NHCOCH₂——NCH₃(CH₂)₂OCH₃ —(CH₂)₂N(CH₃)CO— —O(CH₂)₃OH —(CH₂)₃N(CH₃)CO— —S(CH₂)₃CF₃—(CH₂)₄N(CH₃)CO—

—(CH₂)₂NHCO— —(CH₂)₂CO₂CH₃ —(CH₂)₃N(CH₃)COCH₂—

TABLE 20

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂NHCOOCH₂— —S(CH₂)₃CH₃ —(CH₂)₂NHSO₂——S(CH₂)₂OH —(CH₂)₃NHSO₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂NHSO₂(CH₂)₂— —O(CH₂)₃CF₃—(CH₂)₃NHSO₂CH₂— —S(CH₂)₂OCH₃ —(CH₂)₂N(CH₃)SO₂— —NH(CH₂)₂OCH₃—(CH₂)₃N(CH₃)SO₂— —NCH₃(CH₂)₂OCH₃ —(CH₂)₄N(CH₃)SO₂— —O(CH₂)₃OH—(CH₂)₂N(CH₃)SO₂CH₂— —S(CH₂)₃CF₃ —(CH₂)₂NHCONH—

—(CH₂)₂NHSO₂CH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₃NHCONH—

TABLE 21

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂NHCSNH— —S(CH₂)₃CH₃ —(CH₂)₃NHCSNH——S(CH₂)₂OH —(CH₂)₄NHCSNH— —(CH₂)₂CO₂CH₃ —(CH₂)₂CO— —O(CH₂)₃CF₃—(CH₂)₃CO— —S(CH₂)₂OCH₃ —(CH₂)₄CO— —NH(CH₂)₂OCH₃ —CH₂OCH₂——NCH₃(CH₂)₂OCH₃ —CH₂CO(CH₂)₂— —O(CH₂)₃OH —(CH₂)₂COCH₂— —S(CH₂)₃CF₃—(CH₂)₂CO(CH₂)₂—

—CH₂CO— —(CH₂)₂CO₂CH₃ —CH₂CONH—

TABLE 22

—R¹⁰ —L¹— —O(CH₂)₂OCH₃ —(CH₂)₂CONH— —S(CH₂)₃CH₃ —(CH₂)₃CONH— —S(CH₂)₂OH—CH₂CONHCH₂— —(CH₂)₂CO₂CH₃ —(CH₂)₂CONHCH₂— —O(CH₂)₃CF₃ —CH₂CON(CH₃)——S(CH₂)₂OCH₃ —(CH₂)₂CON(CH₃)— —NH(CH₂)₂OCH₃ —(CH₂)₃CON(CH₃)——NCH₃(CH₂)₂OCH₃ —CH₂CON(CH₃)CH₂— —O(CH₂)₃OH —CH₂CON(CH₃)(CH₂)₂——S(CH₂)₃CF₃ —(CH₂)₂CON(CH₃)CH₂—

—(CH₂)₃CONH—

TABLE 23

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 24

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 25

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 26

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 27

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 28

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

TABLE 29

—R¹⁰ —R⁹ —O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

—O(CH₂)₃CH₃

—O(CH₂)₂OCH₃

—S(CH₂)₂OH

—(CH₂)₂CO₂CH₃

—O(CH₂)₃CH₃

In the following, the present invention is further explained in detailsreferring to Examples, Comparison Examples and Reference Examples, butthe present invention is not limited thereto. In the following examples,chemical structures are for convenience shown in a form of 8-hydroxytype and it is not differentiated from 8-oxo type.

When otherwise stated, the organic solvent was dried over magnesiumsulfate.

RPHPLC means preparative reverse phase HPLC using Waters Symmetry C8,Xterra or Gemini columns and using, as a mobile phase,

acetonitrile and either aqueous solution of ammonium acetate orammonia or trifluoroacetic acid. The column chromatography was conductedwith the use of silica gel.

Example 1 Synthesis of2-butoxy-8-oxo-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine

To 2-butoxy-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (400 mg, 1.04mmol) in chloroform (10 mL) obtained in Reference Example 2 was addedsodium acetate (283 mg, 1.56 mmol), and bromine (78 μl, 1.56 mmol) wasdropped under ice-cooling thereto, and the mixture was stirred at roomtemperature for 3 hours. To the reaction mixture were added saturatedsodium hydrogen carbonate (1 ml) and saturated sodium thiosulfate (2 ml)and stirred for 10 minutes. The reaction solution was diluted with waterand extracted with chloroform (methanol 5%).

The organic layer was washed with water, saturated brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give a bromo compound. To theobtained bromo compound were added methanol (10 ml) and 2.5N sodiumhydroxide (16 ml), and the mixture was stirred at 85° C. for 1.5 hours.The reaction mixture was diluted with water and acidified withconcentrated hydrochloric acid, and concentrated under reduced pressure.To the residue was added water, and the precipitate was collected byfiltration. Methanol (15 ml) and concentrated sulfuric acid (300 μl)were added thereto and the resultant was heated at 85° C. for 2.5 hours.The reaction solution was concentrated under reduced pressure anddiluted with water, and the resultant was neutralized with saturatedsodium hydrogencarbonate. The precipitated solid was collected byfiltration to give 215 mg (0.54 mmol) of the titled compound as a whitesolid. Yield: 52%.

¹H NMR (DMSO-d₆) δ 9.89 (1H, brs), 7.53 (1H, dd, J=2.4, 8.2 Hz), 7.40(1H, dd, J=7.8, 8.2 Hz), 7.36 (1H, dd, J=1.6. 2.4 Hz), 7.19 (1H, dd,J=1.6, 7.8 Hz), 6.43 (2H, brs), 4.36-4.34 (2H, m), 4.08-4.04 (4H, m),3.82 (3H, s), 1.63-1.60 (2H, m), 1.40-1.35 (2H, m), 0.89 (3H, t, J=7.4Hz).

Example 2 Synthesis of2-butoxy-8-oxo-9-[2-(3-methoxycarbonylmethylphenoxy)ethyl]adenine

From 2-butoxy-9-[2-(3-methoxycarbonylmethylphenoxy)ethyl]adenine 160 mg(0.40 mmol) obtained in Reference Example 3 by the same manner toExample 1, the titled compound was obtained as a white solid in anamount of 49 mg (0.12 mmol). Yield: 29%.

¹H NMR (DMSO-d₆) δ9.90 (1H, s), 7.20 (1H, td, J=1.5, 7.4 Hz), 6.84-6.81(3H, m), 6.43 (2H, brs), 4.24 (2H, t, J=5.8 Hz), 4.12 (2H, t, J=6.6 Hz),4.03 (2H, t, J=5.8 Hz), 3.61 (2H, s), 3.59 (3H, s), 1.66-1.61 (2H, m),1.39-1.35 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Example 2-1 Methyl[3-({[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}methyl)phenyl]acetate

(i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolvedin 7N ammonia-methanol solution, and heated in a sealed flask at 100° C.for 6 hours. The reaction mixture was cooled to room temperature,followed by standing overnight and filtration to give the titledcompound. Yield: 40 g (80%).

¹H NMR δ (CDCl₃) 8.02 (1H, s), 5.94 (2H, bs), 5.71 (1H, dd), 4.15-4.22(1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).

(ii) 2-butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

The compound (40 g) obtained in the step (i) was dissolved in 19% sodiumbutoxide-butanol solution, and heated under reflux for 6 hours. Theobtained suspension was cooled to room temperature, diluted with waterand extracted with diethyl ether. The organic layer was washed withwater, dried and concentrated under reduced pressure. The residue wasdissolved in a mixed solvent of isohexane and diethyl ether tocrystallize. The resulting crystals were collected by filtration to givethe titled compound. Yield: 19 g (64%).

¹H NMR δ (CDCl₃) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t),4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).

(iii) 8-bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

The compound obtained in the above step (ii) (30 g) was dissolved indichloromethane (200 ml), and under stirring at room temperature,N-bromosuccinimide (27 g) was slowly added, followed by stirring at roomtemperature overnight. A 20% aqueous sodium thiosulfate solution wasadded, and the separated aqueous layer was extracted withdichloromethane, and the organic layer was washed with an aqueoussaturated sodium hydrogencarbonate solution and saturated brine andconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with water and saturated brine, and dried. The obtainedsolution was filtered through a silica gel and concentrated underreduced pressure. The residue was dissolved in a mixed solvent ofisohexane and diethy ether to crystallize, which was then collected byfiltration to give 26 g of a product. The filtrate was concentrated andthe residue was purified by column chromatography (ethylacetate:isohexane) to give a product 2.5 g. As the combined products, the titledcompound was obtained totally 28.5 g (75%) as a yellow solid. mp148-150° C.

¹H NMR δ (CDCl₃) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74(1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).

(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-6-amine

Under nitrogen atmosphere, to methanol (400 ml) was added sodium (3.7g). To the obtained solution was added the compound obtained in the step(iii) (28.5 g) and the mixture was heated at 65° C. for 9 hours. Thereaction solution was concentrated under reduced pressure and water (500ml) was added thereto. The separated aqueous layer was extracted withethyl acetate and washed with saturated brine, followed byconcentration. The residue was crystallized from diethyl ether to givethe titled compound. Yield: 14.2 g (98%).

¹H NMR δ (CDCl₃) 5.51 (1H dd), 5.28 (2H, bs), 4.29 (2H, t), 4.11-4.14(4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H,m), 0.97 (3H, t).

(v) 2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate

The compound (24 g) obtained in the step (iv) was dissolved in methanol(300 ml) and trifluoroacetic acid (30 ml) was added thereto, and themixture was stirred at room temperature for 72 hours and concentratedunder reduced pressure. A mixture of methanol and ethyl acetate wasadded thereto to precipitate the titled compound as a white solid.Yield: 21 g (80%).

¹H NMR δ (CD₃OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50(2H, sextet), 0.99 (3H, t).

(vi)2-[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]-1H-isoindol-1,3(2H)-dione

In dimethylformamide, a mixture of the compound obtained in the step (v)(3 g) and potassium carbonate (3.54 g) was stirred at 60° C. for 1 hour.The resultant was cooled to room temperature, and2-(2-bromoethyl)-1H-isoindol-1,3(2H)-dione (2.60 g) was added andstirred at room temperature overnight. Ethyl acetate and water wereadded thereto and the organic layer was separated, washed with saturatedbrine, dried and concentrated under reduced pressure. The residue waspurified by column chromatography (methanol: dichloromethane) to givethe titled compound. Yield: 2.6 g (74%); MS APCI+ve 412 (M+H).

(vii) 9-(2-Aminoethyl)-butoxy-8-methoxy-9H-purin-6-amine

The compound obtained in the step (vi) (1 g) was dissolved in ethanol(10 ml), and hydrazine monohydrate (1 ml) was added thereto. The mixturewas heated under reflux for 2 hours. The resultant was cooled to roomtemperature and concentrated under reduced pressure, and the residue wassuspended in dichloromethane (10 ml) and stirred for 1 hour. Thesuspension was filtered, washed with dichloromethane, and the filtratewas concentrated under reduced pressure to give the titled compound.Yield: 700 mg (99%); MS APCI+ve 282 (M+H).

¹H NMR δ (DMSO d₆) 6.76 (2H, brs), 4.10-4.18 (2H, m), 4.04 (3H, s), 3.81(2H, t), 2.82 (2H, t), 1.62-1.69 (2H, m), 1.34-1.46 (2H, m), 0.92 (3H,t).

(viii) Methyl[3-({[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]amino}methyl)phenyl]acetate

The compound obtained in the step (vii) (200 mg) and methyl(3-formylphenyl)acetate (133 mg) were dissolved in methanol (5 ml) andthe mixture was stirred at room temperature for 4 hours. Sodiumborohydride (32 mg) was added and the mixture was stirred at roomtemperature overnight. To the reaction solution were addeddichloromethane (100 ml) and water (100 ml) and the organic layer wasseparated, washed with water and saturated brine and dried. To theobtained solution was added polymer supported aldehyde resin (300 mg)and the mixture was agitated at room temperature overnight. The resinwas removed by filtration and the filtrate was concentrated underreduced pressure to give the titled compound 200 mg. The product wasused in the next reaction without further purification. MS APCI+ve 444(M+H).

(ix) Methyl[3-({[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}methyl)phenyl]acetate

To the compound obtained in the step (viii) solution (200 mg) inmethanol (5 ml) was added 4N hydrochloric acid-dioxane (1 ml). Themixture was stirred at room temperature overnight and concentrated underreduced pressure. To the residue were added water (3 ml) and an aqueoussaturated sodium hydrogen carbonate solution (3 ml) and extracted withdichloromethane and ethyl acetate. The organic layer was dried andconcentrated under reduced pressure and purified by columnchromatography (methanol: dichloromethane). Crystallization fromdichloromethane/acetonitrile gave the titled compound as a white powder.

Yield: 50 mg (15%); MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 10.34 (1H, brs), 9.04 (2H, brs), 7.31-7.41 (4H, m),4.21 (2H, m), 4.14 (2H, t), 4.05 (2H, brt), 3.69 (3H, s), 3.62 (2H, s),3.30 (2H, m), 1.58-1.68 (2H, m), 1.31-1.44 (2H, m), 0.91 (3H, t).

Example 2-2[3-({[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}methyl)phenyl]aceticacid

To the compound obtained in Example 1 solution (30 mg) in methanol (1ml) was added 5N aqueous sodium hydroxide solution (1 ml) and themixture was stirred at room temperature for 6 hours, followed byconcentration under reduced pressure. Water was added thereto and theresultant was neutralized with acetic acid. The precipitated solid wascollected by filtration to give the titled compound. Yield: 9 mg (31%);MS APCI+ve 415 (M+H).

¹H NMR δ (DMSO d₆) 6.89-7.02 (4H, m), 6.69 (2H, brs), 4.12 (2H, t), 3.73(2H, t, J), 3.57 (2H, s), 3.16 (2H, s), 2.79 (2H, t), 1.57-1.65 (2H, m),1.34-1.41 (2H, m), 0.91 (3H, t).

Example 2-3 Methyl3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate

(i)3-[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]-1H-isoindol-1,3(2H)-dione

Using the compound obtained in Example 1 step (v) and2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione, the titled compound wasobtained by the same manner to Example 2-1 (vi). Yield: 2 g (55%).

¹H NMR δ (DMSO d₆) 7.83 (4H, m), 6.73 (2H, brs), 4.06 (2H, t,), 4.01(3H, s), 3.89 (2H, t), 3.58 (2H, t), 2.07-2.14 (2H, m), 1.55-1.62 (2H,m), 1.31-1.40 (2H, m), 0.90 (3H, t).

(ii) 9-(3-Aminopropyl)-2-butoxy-8-methoxy-9H-purine-6-amine

The titled compound was obtained by using the compound obtained in thestep (i) by the same manner to Example 2-1 step (vii). Yield: 400 mg(50%).

¹H NMR δ (DMSO d₆) 6.77 (2H, brs), 4.16 (2H, t), 4.05 (3H, s), 3.89 (2H,t), 2.46-2.52 (2H, m), 1.61-1.76 (4H, m), 1.35-1.45 (2H, m), 0.92 (3H,t).

(iii) Methyl3-({[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)benzoate

The titled compound was obtained by using the compound obtained in thestep (ii) by the similar manner to Example 2-1 step (viii). This productwas used in the next reaction without further purification. Yield: 250mg (60%); MS APCI+ve 444 (M+H).

(iv) Methyl3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate

The titled compound was obtained by using the compound obtained in thestep (iii) by the similar manner to Example 2-1 step (ix). Yield: 176 mg(43%); m.p. 214-218° C., MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 9.90 (1H, brs), 7.92 (1H, s), 7.80-7.82 (1H, m),7.57-7.59 (1H, m), 7.41-7.45 (1H, m), 6.41 (2H, brs), 4.10 (2H, t), 3.74(3H, s), 3.70-3.72 (4H, m), 2.46-2.55 (2H, m), 1.76-1.90 (2H, m),1.56-1.63 (2H, m), 1.30-1.40 (2H, m), 0.89 (3H, t).

Example 2-43-({[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoicacid

The titled compound was obtained by using the compound obtained inExample 2-3 by the similar manner to Example 2-2. Yield: 64 mg (33%); MSAPCI+ve 415 (M+H).

¹H NMR δ (CD₃OD) 7.89 (1H, s), 7.83-7.86 (1H, m), 7.27-7.39 (2H, m),4.25 (2H, t), 3.91 (2H, t), 3.78 (2H, s), 2.62 (2H, t), 1.96-2.03 (2H,m), 1.68-1.75 (2H, m), 1.42-1.52 (2H, m), 0.98 (3H, t).

Example 2-5 Methyl4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate

(i) Methyl4-({[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)benzoate

The titled compound was obtained by using the compound obtained inExample 2-3 step (ii) and methyl 4-formylbenzoate by the similar mannerto Example 2-3 step (i). Yield: 90 mg; MS APCI+ve 444 (M+H).

(ii) Methyl4-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoate

The titled compound was obtained by using the compound obtained in thestep (i) by the similar manner to Example 2-1 step (ix). Yield: 6 mg(11%); MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 7.87-7.89 (2H, m), 7.43-7.46 (2H, m), 6.43 (2H, brs),4.10 (2H, t), 3.84 (3H, s), 3.71-3.74 (4H, m), 2.44-2.50 (2H, m),1.76-1.83 (2H, m), 1.56-1.64 (2H, m), 1.30-1.40 (2H, m), 0.89 (3H, t).

Example 2-64-({[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)benzoicacid

The titled compound was obtained by using the compound obtained inExample 2-5 by the similar manner to Example 2-2. Yield: 2.6 mg (50%);MS APCI+ve 415 (M+H).

¹H NMR δ (CD₃OD) 7.90-7.93 (2H, m), 7.29-7.32 (2H, m), 4.24-4.26 (2H,m), 3.85-3.93 (2H, m), 3.75 (2H, s), 2.58-2.62 (2H, m), 1.95-2.03 (2H,m), 1.69-1.78 (2H, m), 1.40-1.52 (2H, m), 0.99 (3H, t).

Example 2-7 Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-9H-purin-9-yl)propyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate

(i) Methyl[3-({[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate

The titled compound was obtained by using the compound obtained inExample 2-3 step (ii) and methyl (3-formylphenyl)acetate by the similarmanner to Example 2-1 step (viii).

Yield: 270 mg (61%); MS APCI+ve 458 (M+H).

(ii) Methyl(3-{[[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate

The compound obtained in the step (i) (80 mg) was dissolved inacetonitrile (3 ml) and potassium carbonate (58 mg) was added. Theresultant was stirred at room temperature for 10 minutes and4-(2-chloroethyl)morpholine hydrochloride (39 mg) was added thereto,followed by stirring at 60° C. overnight. The reaction solution wasconcentrated under reduced pressure and purified by RPHPLC to give thetitled compound. MS APCI+ve 571 (M+H).

(iii) Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate

The titled compound was obtained by using the compound obtained in thestep (ii) by the similar manner to Example 2-1 step (ix). Yield: 4 mg(11%); MS APCI+ve 557 (M+H).

¹H NMR δ (CD₃OD) 7.12-7.25 (4H, m), 4.26 (2H, t), 3.88 (2H, t,),3.61-3.67 (13H, m), 2.42-2.63 (10H, m), 1.91-2.01 (2H, m), 1.67-1.78(2H, m), 1.42-1.52 (2H, m), 0.98 (3H, t).

Example 2-8 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}methyl)phenyl]acetate

(i)4-[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)butyl]-1H-isoindole-1,3(2H)-dione

The titled compound was obtained by using the compound obtained inExample 2-1 step (v) and 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione bythe similar manner to Example 2-1 step (vi). Yield: 1.1 g (88%); MSAPCI+ve 440 (M+H).

(ii) 9-(4-Aminobutyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The titled compound was obtained by using the compound obtained in thestep (i) by the similar manner to Example 2-1 step (vii). Yield: 720 mg(94%); MS APCI+ve 310 (M+H).

(iii) Methyl[3-({[4-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)butyl]amino}methyl)phenyl]acetate

The titled compound was obtained by using the compound obtained in thestep (ii) and methyl (3-formylphenyl)acetate, by the similar manner toExample 2-1 step (viii). Yield: 200 mg (42%); MS APCI+ve 472 (M+H).

(iv) Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}methyl)phenyl]acetate

The titled compound was obtained by using the compound obtained in thestep (iii) by the similar manner to Example 2-1 step (ix). Yield: 87 mg(45%); MS APCI+ve 457 (M+H).

¹H NMR δ (DMSO d₆) 7.08-7.26 (4H, m), 6.40 (2H, brs), 4.13 (2H, t),3.59-3.68 (9H, m), 2.46-2.51 (2H, m), 1.58-1.70 (4H, m), 1.31-1.44 (4H,m), 0.91 (3H, t).

Example 2-9 Ethyl2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate

(i) Methyl2-[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethoxy]benzoate

The compound obtained in Example 2-1 step (v) was dissolved indimethylformamide (50 ml), and potassium carbonate (3.52 g) and methyl2-(2-bromoethoxy)benzoate (2.2 g) were added thereto. The mixture wasstirred at room temperature for 96 hours and partitioned between ethylacetate and 2M hydrochloric acid. The organic layer was dried andconcentrated under reduced pressure. The residue was dissolved inmethanol and purified by RPHPLC to give the titled compound. Yield:0.768 g (22%).

(ii) Methyl2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate

The compound obtained in the step (i) (0.76 g) was dissolved in methanol(10 ml) and hydrochloric acid (20 ml) was added thereto. The mixture wasstirred at room temperature for 18 hours and concentrated under reducedpressure to give the titled compound. Yield: 0.562 g (16%).

¹H NMR δ (DMSO d₆) 7.56 (1H, d), 7.48 (1H, t), 7.17 (1H, d), 7.00 (1H,t), 6.40 (2H, s), 4.36 (2H, t), 4.10 (2H, t), 4.06 (2H, t), 3.62 (3H,s), 1.61 (2H, tt), 1.36 (2H, m), 0.90 (3H, t).

(iii)2-[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoicacid

The compound obtained in the step (ii) (0.77 g) was dissolved intetrahydrofuran (7 ml) and methanol (2.3 ml) and 1M lithium hydroxide(2.3 ml) was added thereto and the mixture was stirred at roomtemperature for 16 hours. The reaction solution was concentrated underreduced pressure and diluted with 2M hydrochloric acid and the resultingwhite precipitate was collected by filtration, and dried to give thetitled compound as a solid, 0.65 g. The product was used in the nextreaction without further purification.

(iv) Ethyl2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate

The compound obtained in the step (iii) (50 mg) was dissolved indichloromethane (5 ml) and ethanol (0.008 ml), 4-pyrrolidin-1-ylpyridine(2 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide iodine methyl(42 mg) were added thereto. The resultant was stirred at roomtemperature for 12 hours, and to the reaction solution was added 2 Mhydrochloric acid. The organic layer was separated and concentratedunder reduced pressure. The residue was dissolved in ethanol andpurified by RPHPLC to give the titled compound. Yield: 5.6 mg (10%).

¹H NMR δ (DMSO d₆) 7.54 (1H, d), 7.48 (1H, t), 7.17 (1H, d), 7.01 (1H,t), 6.39 (2H, s), 4.36 (2H, t), 4.11 (2H, t), 4.05 (2H, q), 1.61 (2H,tt), 1.37 (m), 1.18 (3H, t), 0.90 (3H, t).

Example 2-10 3-(Dimethylamino)propyl2-[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethoxy]benzoate

The compound obtained in Example 2-9 step (iii) (50 mg) was dissolved indichloromethane (5 ml), and thereto were added3-(dimethylamino)propane-1-ol (0.016 ml), 4-pyrrolidin-1-ylpyridine (2mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide iodine methyl (42mg). The mixture was stirred at room temperature for 96 hours andapplied to a cartridge of SCX resin. The resin was washed withacetonitrile and the fractions were collected by application of 10%aqueous ammonium solution-acetonitrile, and purified by RPHPLC to givethe titled compound. Yield: 8.9 mg (14%).

¹H NMR δ (DMSO d₆) 7.57 (1H, d), 7.48 (1H, t), 7.18 (1H, d), 7.01 (1H,t), 6.40 (2H, s), 4.36 (2H, t), 4.09 (2H, t), 4.06 (2H, m), 4.04 (2H,m), 2.24 (2H, t), 2.11 (6H, s), 1.69 (2H, m), 1.59 (2H, m), 1.38 (1H,m), 0.90 (3H, t).

Example 2-11 Methyl3-[4-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}sulfonyl)phenyl]propanoate

The compound obtained in Example 2-8 step (ii) (308 mg), methyl3-[4-(chlorosulfonyl)phenyl]propanoate (263 mg) and triethylamine (0.284ml) were mixed under stirring at 60° C. for 1 hour, and then cooled.After concentration under reduced pressure, the residue was purified byRPHPLC. The resulting white substance was dissolved in methanol, and 4Mhydrochloric acid-dioxane was added thereto. The mixture was stirred atroom temperature overnight and then concentrated under reduced pressureto give the titled compound as a white solid. Yield: 124 mg (24%); mp150-152° C., MS APCI+ve 521 (M+H).

¹H NMR δ (DMSO d₆) 10.30-10.24 (1H, m), 7.66 (2H, d), 7.51 (1H, t), 7.42(2H, d), 4.21 (2H, t), 3.63 (2H, t), 3.58 (3H, s), 2.96-2.86 (2H, m),2.80-2.60 (4H, m), 1.72-1.53 (4H, m), 1.48-1.23 (4H, m), 0.99-0.78 (5H,m).

Example 2-123-[4-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl]amino}sulfonyl)phenyl]propionicacid

The compound obtained in Example 2-11 (100 mg) and lithium hydroxide (17mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and themixture was stirred at room temperature for 16 hours. To the reactionsolution was added acetic acid (2 ml) and the mixture was concentratedunder reduced pressure. The residue was purified by RPHPLC andappropriate fractions were concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 40 mg (41%); mp 210-211°C., MS APCI+ve 507 (M+H).

¹H NMR δ (DMSO d₆) 7.66 (2H, d), 7.36 (2H, d), 6.31 (2H, s), 4.18 (2H,t), 3.69 (2H, t), 2.94 (2H, t), 2.78 (2H, t), 2.57-2.51 (5H, m),1.75-1.62 (4H, m), 1.51-1.33 (4H, m), 0.95 (3H, t).

Example 2-13 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-pyrrolidin-1-ylethyl)amino]sulfonyl}phenyl)acetate

(i) 9-(4-Bromobutyl)-2-butoxy-8-methoxy-9H-purine-6-amine

The compound obtained in Example 2-1 step (v) (0.5 g) was added topotassium carbonate (0.92 g) and 1,4-dibromobutane (0.85 ml) indimethylformamide (5 ml), and the mixture was stirred at roomtemperature for 16 hours. To the reaction solution was added brine andthe mixture was extracted with ethyl acetate. The organic layer waswashed with brine and concentrated to dryness. The residue was purifiedby flash column chromatography (ethyl acetate) to give the titledcompound, as a white solid. Yield: 370 mg (70%).

¹H NMR δ (CDCl₃) 5.12 (2H, s), 4.28 (2H, t), 4.12 (3H, s), 3.97 (2H, t),3.44 (2H, t), 2.01-1.69 (6H, m), 1.59-1.40 (2H, m), 0.96 (3H, t).

(ii)2-Butoxy-8-methoxy-9-{4-[(2-pyrrolidin-1-ylethyl)amino]butyl}-9H-purine-6-amine

The compound obtained in the step (i) (370 mg) and(2-pyrrolidin-1-ylethyl)amine (342 mg) were dissolved indimethylformamide (5 ml) and the mixture was stirred at 70° C. for 1hour. The reaction mixture was cooled, filtered and purified by RPHPLC.Appropriate fractions were concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 200 mg (50%); MS APCI+ve406 (M+H).

¹H NMR δ (CDCl₃) 5.05 (2H, s), 4.27 (2H, t), 4.10 (3H, s), 3.94 (2H, t),2.73-2.53 (6H, m), 2.50-2.44 (5H, m), 1.84-1.72 (6H, m), 1.56-1.43 (6H,m), 0.96 (3H, t).

(iii) Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-pyrrolidin-1-ylethyl)amino]sulfonyl}phenyl)acetate

The compound obtained in the step (ii) (232 mg), methyl[3-(chlorosulfonyl)phenyl]acetate (43 mg) and triethylamine (0.08 ml)were stirred in acetonitrile (10 ml) at 60° C. for 1 hour. The reactionmixture was cooled, concentrated under reduced pressure and purified byRPHPLC. Appropriate fractions were concentrated under reduced pressureto give a white solid 190 mg. The obtained solid was dissolved inmethanol (5 ml) and 4M hydrochloric acid-dioxane (2 ml) was addedthereto. The mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure and purified byRPHPLC, and appropriate fractions were concentrated under reducedpressure to give the titled compound as a white solid. Yield: 100 mg(29%); MS APCI+ve 602 (M+H).

¹H NMR δ (DMSO d₆) 9.84 (1H, s), 7.73-7.71 (1H, m), 7.68-7.63 (1H, m),7.54-7.50 (2H, m), 6.39 (2H, s), 4.13 (2H, t), 3.83 (2H, s), 3.66 (2H,t), 3.62 (3H, s), 3.13-3.05 (4H, m), 2.44-2.26 (4H, m), 1.68-1.57 (9H,m), 1.49-1.32 (5H, m), 0.91 (3H, t).

Example 2-14(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-pyrrolidin-1-ylethyl)amino]sulfonyl}phenyl)aceticacid

The compound obtained in Example 2-13 (70 mg) and lithium hydroxide (20mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and by thesame manner to Example 2-12, the titled compound was obtained as a whitesolid. Yield: 35 mg (51%); mp 192-193° C., MS APCI-ve 588 (M−H).

¹H NMR δ (DMSO d₆) 7.69 (1H, s), 7.62 (1H, d), 7.55-7.43 (2H, m), 6.51(2H, s), 4.13 (4H, t), 3.08 (4H, t), 2.43 (4H, t), 2.36-2.30 (4H, m),1.69-1.55 (8H, m), 1.48-1.30 (6H, m), 0.91 (3H, t).

Example 2-15 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-methoxyethyl)amino]sulfonyl}phenyl)acetate

(i)2-Butoxy-8-methoxy-9-{4-[(2-methoxyethyl)amino]butyl}-9H-purine-6-amine

The compound obtained in Example 2-13 step (i) (500 mg) and(2-methoxyethyl)amine (303 mg) were dissolved in acetonitrile (5 ml) andstirred at 80° C. for 1 hour. The reaction mixture was cooled, filteredand purified by RPHPLC to give the titled compound as a white solid.Yield: 270 mg (55%); mp 99-100° C., MS APCI+ve 367 (M+H).

¹H NMR δ (DMSO d₆) 6.77 (2H, s), 4.16 (2H, t), 4.06 (3H, s), 3.83 (2H,t), 3.34-3.31 (3H, m), 3.21 (3H, s), 2.58 (2H, t), 1.75-1.58 (4H, m),1.48-1.26 (6H, m), 0.92 (3H, t).

(ii) 2-Butoxy-8-oxo-9-{4-[(3-methoxycarbonylmethyl)phenylsulfonyl(2-methoxyethyl)amino]butyl}-9H-purine-6-amine

Using the compound obtained in the step (i) (230 mg), methyl[3-(chlorosulfonyl)phenyl]acetate (157 mg) and triethylamine (0.09 ml),the titled compound was obtained as a white solid by the same manner toExample 2-13 step (iii). Yield: 170 mg (48%); mp 182-183° C., MS APCI+ve565 (M+H).

¹H NMR δ (DMSO d₆) 9.86 (1H, s), 7.73 (1H, s), 7.68-7.64 (1H, m),7.56-7.48 (2H, m), 6.41 (2H, s), 4.14 (2H, t), 3.83 (2H, s), 3.69-3.60(5H, m), 3.38-3.30 (2H, m), 3.20 (2H, t), 3.17-3.06 (5H, m), 1.69-1.56(4H, m), 1.52-1.32 (4H, m), 0.92 (3H, t).

Example 2-16(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-methoxyethyl)amino]sulfonyl}phenyl)aceticacid

By the same manner to Example 2-12, using the compound obtained inExample 2-15 (100 mg) and a mixed solution of lithium hydroxide solution(20 mg) in tetrahydrofuran (4 ml) and water (2 ml), the titled compoundwas obtained as a white solid from diethyl ether/isohexane. Yield: 60 mg(61%); mp 171-172° C., MS APC-ve 549 (M−H).

¹H NMR δ (DMSO d₆) 7.67 (1H, s), 7.61-7.40 (4H, m), 6.57 (2H, s), 4.13(2H, t), 3.69-3.60 (2H, m), 3.58 (2H, s), 3.37-3.30 (2H, m), 3.21-3.12(5H, m), 3.08-2.99 (2H, m), 1.68-1.56 (2H, m), 1.48-0.99 (4H, m),0.96-0.77 (6H, m).

Example 2-17 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](methyl)amino]sulfonyl}phenyl)acetate

The compound obtained in Example 2-13 step (i) (417 mg) and a 40%aqueous methylamine solution (2 ml) were dissolved in acetonitrile (5ml) and stirred at 80° C. for 1.5 hour. The reaction mixture was cooled,and concentrated under reduced pressure. The residue was dissolved inacetonitrile (5 ml), and using triethylamine (0.16 ml) and methyl[3-(chlorosulfonyl)phenyl]acetate (278 mg), the titled compound wasobtained as a white solid by the same manner to Example 2-13 step (iii).Yield: 120 mg (21%); MS APCI+ve 521 (M+H).

¹H NMR δ (DMSO d₆) 7.69 (1H, s), 7.65-7.61 (2H, m), 7.57-7.53 (2H, m),6.40 (2H, s), 4.14 (2H, t), 3.84 (2H, s), 3.67 (2H, t), 3.63 (3H, s),2.96 (2H, t), 2.62 (3H, s), 1.69-1.58 (4H, m), 1.49-1.33 (4H, m), 0.91(3H, t).

Example 2-18(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](methyl)amino]sulfonyl}phenyl)aceticacid

The compound obtained in Example 2-17 (100 mg) and lithium hydroxide (20mg) were added to tetrahydrofuran (4 ml) and water (2 ml), followed byconducting a reaction by the same manner to Example 2-12, the titledcompound was obtained as a white solid from diethyl ether/isohexane.Yield: 43 mg (64%); mp 171-172° C., MS APC+ve 507 (M+H).

¹H NMR δ (DMSO d₆) 7.63 (1H, s), 7.56-7.43 (3H, m), 6.61 (2H, s), 4.13(2H, t), 3.67 (2H, t), 3.54 (2H, s), 2.88 (2H, t), 2.59 (3H, s),1.70-1.57 (4H, m), 1.48-1.30 (4H, m), 0.91 (3H, t).

Example 2-19 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)phenyl]acetate

The compound obtained in Example 2-13 step (i) (417 mg), triethylamine(0.312 ml) and N,N,2,2-tetramethylpropane-1,3-diamine (146 mg) weredissolved in acetonitrile (5 ml) and stirred at 100° C. for 4 hours. Thereaction mixture was cooled and concentrated under reduced pressure andpurified by RPHPLC. Appropriate fractions were concentrated underreduced pressure to give a residue 190 mg. The residue was dissolved inacetonitrile (5 ml), and using triethylamine (0.13 ml) and methyl[3-(chlorosulfonyl)phenyl]acetate (112 mg), the titled compound wasobtained as a white solid by the same manner to Example 2-13 step (iii).Yield: 83 mg (12%); MS APCI+ve 620 (M+H).

¹H NMR δ (DMSO d₆) 9.82 (1H, s), 7.71 (1H, s), 7.65-7.61 (1H, m),7.52-7.45 (2H, m), 6.40 (2H, s), 4.13 (2H, t), 3.82 (2H, s), 3.62 (3H,s), 3.57 (2H, t), 3.07-3.01 (2H, m), 2.95 (2H, s), 2.17 (6H, s), 2.04(2H, s), 1.68-1.57 (2H, m), 1.55-1.31 (6H, m), 0.91 (3H, t), 0.84 (6H,s).

Example 2-20[3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)phenyl]aceticacid

The compound obtained in Example 2-19 (0.165 g) and lithium hydroxide(45 mg) were added to tetrahydrofuran (4 ml) and water (2 ml). The samemanner to Example 2-12 was conducted to give the titled compound as awhite solid. Yield: 80 mg (51%); mp 175-176° C., MS APC-ve 604 (M−H).

¹H NMR δ (DMSO d₆) 7.74-7.71 (1H, m), 7.64-7.60 (1H, m), 7.58-7.53 (1H,m), 7.51-7.45 (1H, m), 6.63 (2H, s), 4.19 (3H, t), 3.67 (2H, s),3.10-3.03 (2H, m), 2.99 (2H, s), 2.22 (6H, s), 2.10 (2H, s), 1.74-1.63(2H, m), 1.62-1.38 (8H, m), 0.97 (3H, t), 0.90 (6H, s).

Example 2-21 Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}sulfonyl)phenyl]acetate

The compound obtained in Example 2-3 step (ii) (240 mg), triethylamine(0.12 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (204 mg) weredissolved in acetonitrile (5 ml), and the same manner to Example 2-13step (iii) was conducted to give the titled compound as a white solid.Yield: 35 mg (9%); mp 218-219° C., MS APCI+ve 493 (M+H).

¹H NMR δ (DMSO d₆) 7.71-7.61 (2H, m), 7.54 (1H, s), 7.43-7.20 (3H, m),6.73 (1H, s), 4.16-4.09 (1H, m), 3.84 (1H, s), 3.67 (3H, s), 2.81-2.71(1H, m), 2.51 (2H, s), 1.83-1.69 (2H, m), 1.68-1.56 (2H, m), 1.45-1.30(2H, m), 1.14-1.05 (2H, m), 0.95-0.84 (3H, m).

Example 2-22 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxy-2-methylpropyl)amino]sulfonyl}phenyl)acetate

The compound obtained in Example 2-13 step (i) (371 mg) and1-amino-2-methylpropane-2-ol (400 mg) were dissolved in acetonitrile (5ml) and the same manner to Example 2-19 using triethylamine (0.055 ml)and methyl [3-(chlorosulfonyl)phenyl]acetate (93 mg) was conducted togive the titled compound as a white solid. Yield: 140 mg (24%); mp192-193° C., MS APCI+ve 579 (M+H).

¹H NMR δ (DMSO d₆) 9.81 (1H, s), 7.71 (1H, s), 7.65-7.61 (1H, m),7.50-7.42 (2H, m), 6.40 (2H, s), 4.46 (1H, s), 4.13 (2H, t), 3.81 (2H,s), 3.62 (3H, s), 3.58-3.52 (2H, m), 3.25-3.17 (2H, m), 1.71-1.54 (2H,m), 1.52-1.32 (7H, m), 1.10 (6H, s), 0.92 (3H, t).

Example 2-23(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxy-2-methylpropyl)amino]sulfonyl}phenyl)acetic acid

By the same manner to Example 2-12, the compound obtained in Example2-22 (70 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran(4 ml) and water (2 ml) and the mixture was stirred at room temperaturefor 24 hours. The reaction mixture was concentrated under reducedpressure and partitioned between 2M hydrochloric acid and ethyl acetate.The aqueous layer was extracted with ethyl acetate and the combinedorganic layer was dried and concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 23 mg (34%); MS APCI+ve 565(M+H).

¹H NMR δ (DMSO d₆) 10.08 (1H, s), 7.69 (1H, s), 7.64-7.59 (1H, m), 4.18(2H, t), 3.69 (2H, s), 3.61-3.53 (2H, m), 3.24-3.16 (2H, m), 3.03 (2H,s), 1.70-1.59 (2H, m), 1.54-1.34 (8H, m), 1.09 (6H, s), 0.92 (3H, t).

Example 2-24 Methyl[3-({[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}sulfonyl)phenyl]acetate

The compound obtained in Example 2-1 step (vii) (245 mg), triethylamine(0.13 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (217 mg) weredissolved in acetonitrile (5 ml) and the same manner to Example 2-13step (iii) was conducted to give the titled compound as a white solid.Yield: 40 mg (9%); MS APCI+ve 479 (M+H).

¹H NMR δ (DMSO d₆) 7.83 (1H, t), 7.69-7.59 (2H, m), 7.52-7.47 (2H, m),6.48 (2H, s), 4.15 (2H, t), 3.80 (5H, s), 3.61 (3H, s), 3.14-3.03 (2H,m), 1.70-1.57 (2H, m), 1.46-1.31 (2H, m), 0.92 (2H, t).

Example 2-25 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][(2R)-2,3-dihydroxypropyl]amino}sulfonyl)phenyl]acetate

The compound obtained in Example 2-13 step (i) (400 mg),(2R)-3-aminopropane-1,2-diol (200 mg) were dissolved in acetonitrile (5ml) and the gummy residue 230 mg was obtained by the same manner toExample 2-13 step (ii). The residue was dissolved in acetonitrile (10ml) and the same manner to Example 2-13 step (iii) was conducted usingtriethylamine (0.090 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate(150 mg) to give the titled compound as a white solid. Yield: 170 mg(27%); MS APCI+ve 581 (M+H).

¹H NMR δ (DMSO d₆) 9.83 (1H, s), 7.71 (1H, s), 7.66-7.64 (2H, m),7.54-7.45 (2H, m), 6.40 (2H, s), 4.75 (1H, d), 4.57 (1H, t), 4.14 (2H,t), 3.82 (2H, s), 3.62 (3H, s), 3.30-3.05 (6H, m), 2.94-2.86 (1H, m),1.67-1.32 (6H, m), 0.92 (3H, t).

Example 2-26[3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][(2R)-2,3-dihydroxypropyl]amino}sulfonyl)phenyl]aceticacid

The compound obtained in Example 2-25 (100 mg) and lithium hydroxide (20mg) were added to tetrahydrofuran (5 ml) and water (2 ml), and the samemanner to Example 2-12 was conducted to give the titled compound as awhite solid. Yield: 58 mg (60%); MS APCI+ve 567 (M+H).

¹H NMR δ (DMSO d₆) 7.66 (1H, s), 7.56-7.52 (1H, m), 7.50-7.47 (1H, m),7.43-7.38 (1H, m), 6.55 (2H, s), 4.13 (2H, t), 3.63 (2H, t), 3.50 (2H,s), 3.39-3.02 (8H, m), 1.67-1.24 (8H, m), 0.91 (3H, t).

Example 2-27 Methyl3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)benzoate

The compound obtained in Example 2-13 step (i) (500 mg) andN,N,2,2-tetramethylpropane-1,3-diamine (1.5 ml) were dissolved inacetonitrile (10 ml) and the reaction was conducted by the same mannerto Example 2-13 step (ii) to give gummy residue 383 mg astrifluoroacetate. The residue was dissolved in acetonitrile (10 ml), andtriethylamine (0.3 ml) and 3-(chlorosulfonyl)benzoic acid (158 mg) wereadded thereto and the mixture was stirred at 80° C. for 2 hours. Thereaction mixture was cooled, concentrated under reduced pressure andpurified by RPHPLC. Appropriate fractions were concentrated underreduced pressure to give a solid residue 170 mg. The residue wasdissolved in methanol (5 ml) and 4M hydrochloric acid-dioxane (2 ml) wasadded and stirred at room temperature for 24 hours, and thentrimethylsilyl chloride (2 ml) were added thereto and the mixture wasstirred at room temperature for further 72 hours. The reaction mixturewas concentrated under reduced pressure and purified by RPHPLC.Appropriate fractions were concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 8 mg (5%); MS APCI+ve 606(M+H).

¹H NMR δ (DMSO d₆) 9.85 (1H, s), 8.21 (1H, t), 8.17-8.13 (1H, m),8.05-8.01 (1H, m), 7.69 (1H, t), 6.41 (2H, s), 4.11 (2H, t), 3.90 (3H,s), 3.58 (2H, t), 3.12-3.06 (2H, m), 2.18 (6H, s), 2.04 (2H, s),1.67-1.55 (2H, m), 1.52-1.28 (8H, m), 0.91 (3H, t), 0.85 (6H, s).

Example 2-283-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}sulfonyl)benzoicacid

The titled compound was obtained as a white solid by the same manner toExample 2-27. Yield: 38 mg (23%); MS ESI+ve 592 (M+H).

¹H NMR δ (DMSO d₆) 9.86 (1H, s), 8.83 (1H, s), 7.70-7.60 (2H, m),7.40-7.26 (2H, m), 6.41 (2H, s), 4.14-4.10 (2H, m), 4.12 (2H, t),3.55-3.37 (4H, m), 3.05-2.96 (2H, m), 2.88-2.80 (6H, m), 1.68-1.58 (2H,m), 1.44-1.27 (6H, m), 1.10 (6H, s), 0.92 (3H, t).

Example 2-29 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate

The compound obtained in Example 2-13 step (i) (830 mg) and(3-morpholin-4-ylpropyl)amine (3 ml) were dissolved in acetonitrile (10ml) and stirred at 80° C. for 3 hours. The reaction mixture was cooledand concentrated under reduced pressure, and purified by RPHPLC.Appropriate fractions ware concentrated under reduced pressure to givecolorless gummy residue 600 mg. The residue was dissolved inacetonitrile (20 ml), and potassium carbonate (380 mg) and methyl[3-(bromomethyl)phenyl]acetate (336 mg) were added thereto. The mixturewas stirred at room temperature for 16 hours. The reaction mixture waspartitioned between ethyl acetate and water. Further, an aqueous layerwas extracted with ethyl acetate and the combined organic layer wasdried and concentrated under reduced pressure. The resulting gummyresidue was purified by RPHPLC. Appropriate fractions were concentratedunder reduced pressure, and the obtained gummy residue was dissolved inmethanol (5 ml) and 4M hydrochloric acid was added thereto and themixture was stirred at room temperature for 24 hours. The reactionmixture was concentrated under reduced pressure and purified by RPHPLC.Appropriate fractions were concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 460 mg (57%); MS APCI+ve584 (M+H).

¹H NMR δ (CDCl₃) 7.25-7.15 (3H, m), 7.14-7.10 (1H, m), 5.67 (2H, s),4.26 (2H, t), 3.83 (2H, t), 3.69 (3H, s), 3.67 (2H, t), 3.61 (2H, s),3.49 (2H, s), 2.46-2.23 (10H, m), 1.83-1.39 (12H, m), 0.96 (3H, t).

Example 2-30(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-yl)butyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)aceticacid

The compound obtained in Example 2-29 (200 mg) and lithium hydroxide(100 mg) were added to tetrahydrofuran (15 ml) and water (5 ml) and thesame manner as Example 2-12 was conducted to give the titled compound asa white solid. Yield: 130 mg (66%); MS APCI+ve 570 (M+H).

¹H NMR δ (CDCl₃) 7.30 (1H, s), 7.15-7.08 (2H, m), 7.03-6.95 (1H, m),6.10 (1H, s), 4.20 (2H, t), 3.74 (2H, s), 3.64 (2H, s), 2.62-2.32 (12H,m), 1.76-1.58 (8H, m), 1.54-1.37 (6H, m), 1.21 (2H, t), 0.94 (3H, t).

Example 2-31 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}methyl)phenyl]acetate

Using the compound obtained in Example 2-13 step (i) (350 mg),N,N,2,2-tetramethylpropane-1,3-diamine (1 ml), potassium carbonate (500mg) and methyl[3-(bromomethyl)phenyl]acetate (200 mg), the same mannerto Example 2-29 was conducted to give the titled compound as a whitesolid. Yield: 60 mg (13%); MS APCI+ve 570 (M+H).

¹H NMR δ (CDCl₃) 7.25-7.19 (3H, m), 7.13-7.08 (1H, m), 5.63 (2H, s),5.63 (2H, s), 4.26 (2H, t), 3.78 (2H, t), 3.69 (3H, s), 3.62 (2H, s),3.59 (2H, s), 2.38 (2H, t), 2.31 (2H, s), 2.24 (6H, s), 1.79-1.43 (8H,m), 0.96 (3H, t), 0.86 (6H, s).

Example 2-32[3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}methyl)phenyl]aceticacid

Using the compound obtained in Example 2-31 (50 mg) and lithiumhydroxide (15 mg), the same manner to Example 2-12 was conducted to givethe titled compound as a white solid. Yield: 10 mg (21%); mp 189-190°C., MS APCI+ve 556 (M+H).

¹H NMR δ (DMSO d₆) 7.78-7.56 (1H, m), 7.28-7.09 (3H, m), 5.90 (2H, s),4.26-4.17 (2H, m), 3.77-3.68 (2H, m), 3.58 (2H, s), 3.54 (2H, s),2.44-2.10 (13H, m), 1.81-1.55 (4H, m), 1.50-1.38 (5H, m), 0.95 (3H, t),0.90 (6H, s).

Example 2-33 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl)phenyl]acetate

Using the compound obtained in Example 2-13 step (i) (400 mg),1-(3-aminopropyl)pyrrolidin-2-on (1 ml), potassium carbonate (175 mg)and methyl [3-(bromomethyl)phenyl]acetate (175 mg), the same manner toExample 2-29 was conducted to give the titled compound as a white solid.Yield: 200 mg (48%); mp 115-116° C., MS APCI+ve 582 (M+H).

¹H NMR δ (CDCl₃) 10.46 (1H, s), 7.24-7.10 (4H, m), 5.88 (2H, s), 4.27(2H, t), 3.87 (2H, t), 3.68 (3H, s), 3.61 (2H, s), 3.48 (2H, s), 3.27(2H, t), 3.22-3.18 (2H, m), 2.41-2.32 (6H, m), 2.01-1.90 (2H, m),1.82-1.55 (6H, m), 1.52-1.41 (4H, m), 0.96 (3H, t).

Example 2-34[3-({[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl)phenyl]aceticacid

The compound obtained in Example 2-33 (50 mg) and lithium hydroxide (20mg) were added to tetrahydrofuran (5 ml) and water (1 ml), and the samemanner to Example 2-12 was conducted to give the titled compound as awhite solid. Yield: 39 mg (80%); MS APCI+ve 568 (M+H).

¹H NMR δ (CDCl₃) 7.41-7.36 (1H, m), 7.22-7.06 (3H, m), 5.71 (2H, s),4.23 (2H, t), 3.79 (2H, t), 3.58 (2H, s), 3.53 (2H, s), 3.29-3.21 (4H,m), 2.60-2.57 (1H, m), 2.49-2.38 (5H, m), 2.31 (2H, t), 1.97-1.89 (2H,m), 1.79-1.60 (6H, m), 1.53-1.39 (4H, m), 0.95 (3H, t).

Example 2-35 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate

Using the compound obtained in Example 2-13 step (i) (500 mg),(2-morpholin-4-ylethyl)amine (1 ml), potassium carbonate (206 mg) andmethyl [3-(bromomethyl)phenyl]acetate (180 mg), the same manner toExample 2-29 was conducted to give the titled compound as a white solid.Yield: 100 mg (13%); mp 189-190° C., MS APCI+ve 570 (M+H).

¹H NMR δ (DMSO d₆) 7.26-7.07 (4H, m), 6.38 (2H, s), 4.12 (2H, t),3.72-3.61 (6H, m), 3.59 (3H, s), 3.51-3.45 (8H, m), 2.45-2.29 (2H, m),2.25-2.14 (2H, m), 1.90-1.75 (2H, m), 1.68-1.26 (8H, m), 0.90 (3H, t).

Example 2-36(3-{[[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)aceticacid

The compound obtained in Example 2-35 (50 mg) lithium hydroxide (20 mg)were added to tetrahydrofuran (5 ml) and water (1 ml), and the samemanner to Example 2-12 was conducted to give the titled compound as awhite solid. Yield: 35 mg (76%); MS APCI+ve 556 (M+H).

¹H NMR δ (DMSO d₆) 9.95 (1H, s), 7.25-7.07 (4H, m), 6.43 (2H, s), 4.14(2H, t), 3.65 (2H, t), 3.53-3.46 (6H, m), 2.51 (2H, s), 2.47-2.37 (4H,m), 2.35-2.21 (6H, m), 1.70-1.59 (4H, m), 1.44-1.32 (4H, m), 0.91 (3H,t).

Example 2-37 Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate

(i) 9-(3-bromopropyl)-2-butoxy-8-methoxy-9H-purine-6-amine

The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate(3.7 g) and 1,3-dibromopropane (2.85 ml) were added to dimethylformamide(5 ml), and the same manner to Example 2-13 step (i) was conducted togive the titled compound as a white solid. Yield: 1.0 g (50%).

¹H NMR δ (CDCl₃) 5.18 (2H, s), 4.28 (2H, t), 4.12 (3H, s), 4.09 (2H, t),3.38 (2H, t), 2.38-2.31 (2H, m), 1.80-1.73 (2H, m), 1.54-1.45 (2H, m),0.96 (3H, t).

(ii) Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate

Using the compound obtained in the step (i) (481 mg),(3-morpholin-4-ylpropl)amine (1.5 ml), potassium carbonate (150 mg) andmethyl [3-(bromomethyl)phenyl]acetate (125 mg), the same manner toExample 2-29 was conducted to give the titled compound as a white solid.Yield: 57 mg (7%); mp 200-201° C., MS APCI+ve 570 (M+H).

¹H NMR δ (DMSO d₆) 7.26-7.07 (4H, m), 6.38 (2H, s), 4.12 (2H, t),3.72-3.61 (6H, m), 3.59 (3H, s), 3.51-3.45 (8H, m), 2.45-2.29 (2H, m),2.25-2.14 (2H, m), 1.90-1.75 (2H, m), 1.68-1.26 (8H, m), 0.90 (3H, t).

Example 2-38 Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][2-(1H-tetrazol-5-yl)ethyl]amino}methyl)phenyl]acetate

The compound obtained in Example 2-13 step (i) (500 mg) and3-aminopropane nitrile (471 mg) were dissolved in acetonitrile (10 ml)and stirred at 80° C. for 2 hours. The reaction mixture was cooled,concentrated under reduced pressure and purified by RPHPLC. Appropriatefractions were concentrated under reduced pressure to give a white solid220 mg. The residue was dissolved in methanol, (3-formylphenyl)acetate(109 mg) was added thereto and the mixture was stirred at roomtemperature for 1 hour. Sodium borohydride (28 mg) was added thereto andthe mixture was stirred at room temperature for further 2 hours. To thereaction mixture was added acetic acid (2 ml) and the mixture wasconcentrated under reduced pressure and purified by RPHPLC. Appropriatefractions were concentrated under reduced pressure to give a solid 170mg. The obtained solid was dissolved in toluene (8 ml), andmethylsilylazide (0.06 ml) and dibutyl tin oxide (72 mg) were addedthereto, followed by stirring at 110° C. for 24 hours. The reactionmixture was cooled, concentrated under reduced pressure and purified byRPHPLC. Appropriate fractions were concentrated under reduced pressureto give a gummy substance. The gummy substance was dissolved in methanol(5 ml), and 4M hydrochloric acid-dioxane (2 ml) was added thereto,followed by stirring at room temperature for 24 hours. The reactionmixture was concentrated under reduced pressure and purified by RPHPLC.Appropriate fractions were concentrated under reduced pressure to givethe titled compound as a white solid. Yield: 10 mg (2%); MS APCI+ve 553(M+H).

¹H NMR δ (CDCl₃) 7.23-6.98 (4H, m), 4.24 (2H, t), 3.97-3.86 (2H, m),3.67 (3H, s), 3.59 (2H, s), 3.22-3.10 (2H, m), 3.01-2.89 (2H, m),2.77-2.60 (2H, m), 2.29-1.95 (2H, m), 1.86-1.66 (4H, m), 1.62-1.31 (4H,m), 0.94 (3H, t)

Example 2-39 Methyl(3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)acetate

(i) 9-(2-Bromoethyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate(3.7 g) and 1,2-dibromoethane (0.6 ml) were added to dimethylformamide(20 ml), and the same manner to Example 2-13 step (i) was conducted togive the titled compound as a cream colored solid. Yield: 1.2 g (62%).

¹H NMR δ (CDCl₃) 5.15 (2H, s), 4.30 (4H, m), 4.13 (3H, s), 3.65 (2H, t),1.82-1.72 (2H, m), 1.56-1.43 (2H, m), 0.97 (3H, t).

(ii) Methyl(3-{[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]thio}phenyl)acetate

The compound obtained in the step (i) (200 mg), methyl(3-mercaptophenyl)acetate (110 mg) and potassium carbonate (100 mg) werestirred in dimethylformamide (2 ml) at room temperature. After 1 hour,the reaction was completed and purification by RPHPLC was conducted togive the titled compound as a colorless solid. Yield: 150 mg (58%).

¹H NMR δ (DMSO d₆) 7.28-7.21 (3H, m), 7.11-7.06 (1H, m), 6.74 (2H, s),4.13 (2H, t), 4.07-4.00 (2H, m), 4.00 (3H, s), 3.66 (2H, s), 3.61 (3H,s), 3.38-3.27 (2H, m), 1.64 (2H, quintet), 1.39 (2H, sextet), 0.91 (3H,t).

(iii) Methyl(3-{[2-(6-amino2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)acetate

The compound obtained in the step (ii) (135 mg) and 6N hydrochloric acidsolution (2 ml) in acetonitrile (10 ml) were stirred under heating for17 hours. The reaction mixture was concentrated to dryness, and methanol(20 ml) and 4N hydrochloric acid-dioxane were added thereto. The mixturewas heated under reflux for 1 hour, and then the solvent was removed bydistillation under reduced pressure. The residue was partitioned betweenan aqueous saturated sodium hydrogen carbonate solution and ethylacetate. The organic layer was dried and concentrated under reducedpressure and purified by RPHPLC to give the titled compound, as acolorless solid. Yield: 13 mg (10%); mp 232-233° C., MS APCI+ve 432(M+H).

¹H NMR δ (DMSO d₆+CD₃OD) 7.24 (2H, m), 7.17 (2H, t), 7.04 (1H, d), 4.22(2H, t), 4.06 (2H, t), 3.67 (3H, s), 3.58 (2H, s), 3.37 (2H, t), 1.73(2H, quintet), 1.48 (2H, sextet), 0.98 (3H, t).

Example 2-40(3-{[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)aceticacid

(i)(3-{[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]thio}phenyl)aceticacid

The same manner to Example 2-39 step (ii) using (3-mercaptophenyl)aceticacid (100 mg) was conducted to give the titled compound. Yield: 70 mg(28%); MS APCI+ve 432 (M+H).

¹H NMR δ (DMSO d₆) 7.28-7.22 (3H, m), 7.11-7.07 (1H, m), 6.77 (2H, s),4.14 (2H, t), 4.04 (2H, t), 3.99 (3H, s), 3.55 (2H, s), 3.35 (2H, t),1.64 (2H, quintet), 1.4 (2H, sextet), 0.92 (3H, t).

(ii)(3-{[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]thio}phenyl)aceticacid

The compound obtained in the step (i) (70 mg) was added totetrahydrofuran (10 ml) and 6N hydrochloric acid (2 ml). and the mixturewas heated under reflux for 3 hours. The solvent was removed bydistillation under reduced pressure and purified by RPHPLC to give thetitled compound as a solid. Yield: 40 mg (59%); mp 205-207° C., MSAPCI-ve 416 (M−H).

¹H NMR δ (DMSO d₆) 12.33 (1H, s), 9.85 (1H, s), 7.31-7.20 (3H, m), 7.08(1H, d), 6.40 (2H, s), 4.12 (2H, t), 3.89 (2H, t), 3.55 (2H, s), 3.30(2H, t), 1.64 (2H, quintet), 1.38 (2H, sextet), 0.92 (3H, t).

Example 2-41 Methyl(3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}phenyl)acetate

(i) Methyl {3-[(2-bromoethyl)amino]phenyl}acetate

Methyl (3-aminophenyl)acetate (1 g) and 1,2-dibromoethane (5 ml) wereheated at 100° C. for 5 hours. After cooling, the resultant was purifiedby column chromatography (ethyl acetate:isohexane 7:3) to give thetitled compound as an oil. Yield: 280 mg (17%).

¹H NMR δ (CDCl₃) 7.14 (1H, t), 6.66 (1H, d), 6.59-6.52 (2H, m), 3.69(3H, s), 3.58-3.53 (6H, m).

(ii) Methyl(3-{[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]amino}phenyl)acetate

To a solution of the compound obtained in Example 2-1 step (v) (0.2 g)in dimethylformamide (2 ml) was added potassium carbonate (236 mg) andthen the compound obtained in the step (i) (160 mg) was further addedthereto. The mixture was stirred at room temperature overnight. To thereaction mixture was added water and extracted with ethyl acetate. Theorganic layer was dried, concentrated and purified by RPHPLC to give thetitled compound as a colorless solid. Yield: 200 mg (82%); mp 119-120°C., MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 7.01 (1H, t), 6.77 (2H, s), 6.52 (1H, d), 6.48 (1H,s), 6.43 (1H, d), 5.82 (1H, t), 4.15 (2H, t), 4.05-3.93 (5H, m), 3.60(3H, s), 3.50 (2H, s), 3.39-3.33 (2H, m), 1.65 (2H, quintet), 1.40 (2H,sextet), 0.92 (3H, t).

(iii) Methyl(3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]amino}phenyl)acetate

To the solution of the compound obtained in the step (ii) (200 mg) inmethanol (15 ml) was added 4N dioxane (5 ml) under stirring, and stirredat room temperature for 24 hours, concentrated under reduced pressureand purified by RPHPLC to give the titled compound as a colorless solid.Yield: 13 mg (6.7%); mp 222-223° C., MS APCI+ve 415 (M+H).

¹H NMR δ (DMSO d₆+CD₃OD) 7.01 (1H, t), 6.59-6.43 (3H, m), 4.20 (2H, t),4.01-3.91 (2H, m), 3.64 (3H, s), 3.49 (2H, s), 3.46-3.38 (2H, m), 1.70(2H, quintet), 1.45 (2H, sextet), 0.96 (3H, t).

Example 2-42 Methyl(3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}phenyl)acetate

(i) Methyl {3-[(3-bromopropyl)amino]phenyl}acetate

Using 1,3-dibromopropane (1.7 ml) and methyl (3-aminophenyl)acetate (280mg), the same manner to Example 2-41 step (i) was conducted to give thetitled compound as a solid. Yield: 200 mg (70%).

¹H NMR δ (CDCl₃) 7.15-7.11 (1H, m), 6.62 (1H, d), 6.56-6.5 (2H, m), 3.69(3H, s), 3.56-3.48 (4H, m), 3.33 (2H, t), 2.15 (2H, quintet).

(ii) Methyl(3-{[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}phenyl)acetate

Using the compound obtained in the step (i) (170 mg), the same manner toExample 2-41 step (ii) was conducted to give the titled compound as asolid. Yield: 220 mg (87%); mp 129-130° C., MS APCI+ve 443 (M+H).

¹H NMR δ (DMSO d₆) 6.99 (1H, t), 6.44-6.38 (3H, m), 4.15 (2H, t), 4.02(3H, s), 3.94 (2H, t), 3.59 (3H, s), 3.48 (2H, s), 2.96 (2H, t), 1.94(2H, quintet), 1.64 (2H, quintet), 1.39 (2H, sextet), 0.91 (3H, t).

(iii) Methyl(3-{[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}phenyl)acetate

Using the compound obtained in the step (ii), the same manner to Example2-41 step (iii) was conducted to give the titled compound as a solid.Yield: 63 mg (31%); mp 208-209° C., MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 9.86 (1H, s), 6.98 (1H, t), 6.46-6.35 (5H, m), 5.61(1H, t), 4.13 (2H, t), 3.76 (2H, t), 3.58 (3H, s), 3.47 (2H, s), 3.00(2H, q), 1.90 (2H, quintet), 1.63 (2H, quintet), 1.38 (2H, sextet), 0.91(3H, t).

Example 2-43(3-{[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}phenyl)aceticacid

The compound obtained in Example 2-42 (70 mg) was dissolved in methanol(5 ml) and a lithium hydroxide solution (45 mg) in water (5 ml) wasadded thereto. The same manner to Example 2-12 was conducted to give thetitled compound as a colorless solid. Yield: 14 mg (21%); mp 247° C., MSAPCI-ve 413 (M−H).

¹H NMR δ (DMSO d₆) 6.85 (1H, t), 6.73-6.45 (2H, brs), 6.35 (2H, d), 6.28(1H, d), 5.42 (1H, t), 4.11 (2H, t), 3.71 (2H, t), 3.08 (2H, s),2.99-2.88 (2H, m), 1.92-1.80 (2H, m), 1.63 (2H, quintet), 1.39 (2H,sextet), 0.92 (3H, t).

Example 2-44 Methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]amino}methyl)phenyl]acetate

Using the compound obtained in Example 2-7 step (i) (180 mg), the samemanner to Example 2-41 step (iii) was conducted to give the titledcompound as a solid. Yield: 55 mg (32%); MS APCI+ve 443 (M+H).

¹H NMR δ (DMSO d₆) 7.29 (4H, m), 7.19 (1H, d), 6.58 (2H, s), 6.53 (3H,s), 4.13 (2H, t), 3.85 (2H, s), 3.73 (2H, t), 3.66 (2H, s), 3.60 (3H,s), 2.69 (2H, t), 1.90 (2H, quintet), 1.63 (2H, quintet), 1.38 (2H,sextet), 0.91 (3H, t).

Example 2-45([3-({[3-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)propyl]amino}methyl)phenyl]aceticacid

Using the compound obtained in Example 2-44 (30 mg), the same manner asExample 2-12 was conducted to give the titled compound. Yield: 26 mg(89%); MS APCI+ve 429 (M+H).

¹H NMR δ (DMSO d₆) 7.45 (1H, d), 7.40 (1H, s), 7.36 (1H, t), 7.30 (1H,d), 4.42 (2H, t), 4.08 (2H, s), 3.83 (2H, t), 3.58 (2H, s), 2.95 (2H,t), 2.16-2.05 (2H, m), 1.73 (2H, quintet), 1.42 (2H, sextet), 0.94 (3H,t).

Example 2-46 Methyl(3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](2-methoxyethyl)amino]methyl}phenyl)acetate

(i) Methyl (3-{[(2-methoxyethyl)amino]methyl}phenyl)acetate oxalate

Under stirring at 0° C., to (2-methoxyethyl)amine (2.5 ml) was addedmethyl [3-(bromomethyl)phenyl]acetate (0.5 g) and the mixture wasstirred for 5 minutes. The resultant was purified by columnchromatography (dichloromethane: 7N-ammonia-methanol, 9:1), and 1Noxalic acid in ethanol was added thereto to give the titled compound asa monooxalate. Yield: 630 mg (93%).

¹H NMR δ (DMSO d₆) 7.42-7.27 (4H, m), 4.11 (2H, s), 3.70 (2H, s), 3.62(3H, s), 3.58 (2H, t), 3.28 (3H, s), 3.05 (2H, t).

(ii) Methyl(3-{[[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl](2-methoxyethyl)amino]methyl}phenyl)acetate

A suspension of the compound obtained in the step (i) (571 mg), thecompound obtained in Example 2-39 step (i) (300 mg) and potassiumcarbonate (730 mg) in dimethylformamide (4 ml) was stirred at 55° C. for4 days. The resultant was cooled and filtrated, and the filtrate waspurified by RPHPLC to give the titled compound as a colorless solid.Yield: 140 mg (32%); MS APCI+ve 501 (M+H).

¹H NMR δ (CDCl₃) 7.17-7.06 (2H, m), 6.98 (2H, d), 6.94 (2H, s), 5.13(2H, s), 4.19 (2H, t), 4.01-3.96 (5H, m), 3.68 (3H, s), 3.63 (2H, s),3.55 (2H, s), 3.38 (2H, t), 3.26 (3H, s), 2.86 (2H, t), 2.73 (2H, t),1.72 (2H, quintet), 1.48 (2H, sextet), 0.95 (3H, t).

(iii) Methyl3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](2-methoxyethyl)amino]methyl}phenyl)acetate

Using the compound obtained in the step (ii) (130 mg), the same mannerto Example 2-41 step (iii) was conducted to give the titled compound asa solid. Yield: 120 mg (95%); MS APCI+ve 487 (M+H).

¹H NMR δ (DMSO d₆) 9.80 (1H, s), 7.15-7.10 (2H, m), 7.07-7.00 (2H, m),6.36 (2H, s), 4.05 (2H, t), 3.76 (2H, t), 3.61 (2H, s), 3.58 (3H, s),3.56 (2H, s), 3.30 (2H, s), 3.14 (3H, s), 2.76 (2H, t), 2.60 (2H, t),1.59 (2H, quintet), 1.35 (2H, sextet), 0.89 (3H, t).

Example 2-47(3-{[[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl](2-methoxyethyl)amino]methyl}phenyl)aceticacid

Using the compound obtained in Example 2-46 (40 mg), the same manner toExample 2-12 was conducted to give the titled compound. Yield: 35 mg(90%); MS APCI+ve 473 (M+H).

¹H NMR δ (DMSO d₆) 7.08 (1H, d), 7.02 (1H, t), 6.89-6.81 (2H, m), 6.64(2H, s), 4.10 (2H, t), 3.72 (2H, t), 3.50 (2H, s), 3.31 (2H, t), 3.23(2H, s), 3.15 (3H, s), 2.74 (2H, t), 2.61 (2H, t), 1.62 (2H, quintet),1.38 (2H, sextet), 0.91 (3H, t).

Example 2-48 Methyl(3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]sulfonyl}phenyl)acetate

(i) Methyl(3-{[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl]sulfonyl}phenyl)acetate

The compound obtained in Example 2-39 step (ii) (200 mg) was dissolvedin water (15 ml) and acetone (20 ml), and Oxone® (610 mg) was addedtogether with sufficient sodium carbonate to maintain basic conditionand stirred at room temperature for 0.5 hour. To the reaction solutionwas added water and the mixture was extracted with ethyl acetate. Theorganic layer was concentrated and the residue was purified by RPHPLC togive the titled compound as a colorless solid. Yield: 90 mg (42%); MSAPCI+ve 478 (M+H).

¹H NMR δ (CD₃OD) 7.64-7.61 (1H, m), 7.60-7.58 (1H, m), 7.50-7.47 (1H,m), 7.40 (1H, t), 4.32 (2H, t), 4.26 (2H, t), 4.09 (3H, s), 3.91 (2H,t), 3.69 (3H, s), 3.67 (2H, s), 1.76 (2H, quintet), 1.51 (2H, sextet),1.00 (3H, t).

(ii) Methyl(3-{[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl]sulfonyl}phenyl)acetate

Using the compound obtained in the step (i) (80 mg), the same manner toExample 2-41 step (iii) was conducted to give the titled compound as acolorless solid. Yield: 30 mg (38%); mp 246-247° C., MS APCI+ve 464(M+H).

¹H NMR δ (DMSO d₆) 9.78 (1H, s), 7.77-7.73 (2H, m), 7.60-7.58 (1H, m),7.53 (1H, t), 6.38 (2H, s), 4.12 (2H, t), 3.98 (2H, t), 3.82 (2H, t),3.78 (2H, s), 3.63 (3H, s), 1.65 (2H, quintet), 1.40 (2H, sextet), 0.93(3H, t).

Example 2-49 Methyl(3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](methyl)amino]methyl}phenyl)acetate

(i) Methyl {3-[(methylamino)methyl]phenyl}acetate oxalate

To a 40% aqueous methylamine solution (10 ml) was added methyl[3-(bromomethyl)phenyl]acetate (3 g). The mixture was stirred for 0.5hour, extracted with ethyl acetate, and concentrated under reducedpressure. The residue was dissolved in ethanol (100 ml) and acetic acid(10 ml). The resulting solution was stirred at room temperature for 1hour in the presence of a 10% palladium-carbon catalyst under hydrogenatmosphere, and then the catalyst was removed by filtration. Thefiltrate was concentrated under reduced pressure and the residue waspartitioned between 2N hydrochloric acid and ethyl acetate. Aftercollecting the aqueous layer, it was made alkaline by potassiumcarbonate and extracted with ethyl acetate. The extract was dried andconcentrated to give an and oil (1 g). To the obtained oil in ethanol (5ml) was added oxalic acid (467 mg) to give the titled compound as acolorless solid. Yield: 1.3 g (37%).

¹H NMR δ (DMSO d₆) 7.41-7.28 (4H, m), 4.09 (2H, s), 3.71 (2H, s), 3.62(3H, s), 2.54 (3H, s).

(ii) Methyl(3-{[[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl](methyl)-amino]methyl}phenyl)acetate

Using the compound obtained in the step (i) (500 mg) and the compoundobtained in Example 2-39 step (i) (300 mg), the same manner as Example2-46 step (ii) was conducted to give the titled compound as a colorlesssolid. Yield: 130 mg (33%); MS APCI+ve 457 (M+H).

¹H NMR δ (CD₃OD) 7.11-7.01 (2H, m), 6.89-6.84 (2H, m), 4.16 (2H, t),4.06-3.99 (5H, m), 3.64 (3H, s), 3.51 (2H, s), 3.46 (2H, s), 2.68 (2H,t), 2.33 (3H, s), 1.68 (2H, quintet), 1.44 (2H, sextet), 0.95 (3H, t).

(iii) Methyl(3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](methyl)amino]methyl}phenyl)acetate

Using the compound obtained in the step (ii) (125 mg), the same mannerto Example 2-41 step (iii) was conducted to give the titled compound asa cream colored solid. Yield: 85 mg (97%); MS APCI+ve 443 (M+H).

¹H NMR δ (DMSO d₆) 9.84 (1H, s), 7.14 (1H, t), 7.06 (1H, d), 7.03-6.96(2H, m), 6.39 (2H, s), 4.06 (2H, t), 3.80 (2H, t), 3.59 (3H, s), 3.56(2H, s), 3.47 (2H, s), 2.63 (2H, t), 2.18 (3H, s), 1.59 (2H, quintet),1.34 (2H, sextet), 0.89 (3H, t).

Example 2-50(3-{[[2-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](methyl)amino]methyl}phenyl)aceticacid

Using the compound obtained in Example 2-49 (60 mg), the same manner toExample 2-12 was conducted to give the titled compound as a solid.Yield: 35 mg (60%); mp 164-166° C., MS APCI-ve 427 (M−H).

¹H NMR δ (DMSO d₆) 9.90 (1H, s), 7.12 (1H, t), 7.06 (1H, d), 7.01-6.95(2H, m), 6.39 (2H, s), 4.06 (2H, t), 3.80 (2H, t), 3.45 (4H, d), 2.64(2H, t), 2.17 (3H, s), 1.59 (2H, quintet), 1.34 (2H, sextet), 0.89 (3H,t).

Example 2-51 Methyl4-[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)-2-hydroxypropoxy]benzoate

(i) tert-Butyl4-[3-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)-2-hydroxypropoxy]benzoate

A suspension of the compound obtained in Example 2-1 step (v) (330 mg),tert-butyl 4-(oxilan-2-ylmethoxy)benzoate (256 mg) and potassiumcarbonate (365 mg) in 2-methylpropane-2-ol (2.5 ml) was heated at 50° C.for 24 hours. The mixture was cooled and partitioned between water andethyl acetate. The organic layer was dried, concentrated under reducedpressure and purified by flash column chromatography (ethylacetate:isohexane, 8:2) to give the titled compound as a colorless oil.Yield: 260 mg (62%); Purity about 80%, MS APCI+ve 488 (M+H).

(ii) Methyl4-[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-yl)-2-hydroxypropoxy]benzoate

Using the compound obtained in the step (i) (260 mg), the same manner toExample 2-41 step (iii) was conducted to give the titled compound, as asolid. Yield: 35 mg (15%); MS APCI+ve 432 (M+H).

¹H NMR δ (DMSO d₆) 9.88 (1H, s), 7.88 (2H, d), 6.96 (2H, d), 6.40 (2H,s), 5.39 (1H, d), 4.36-4.21 (1H, m), 4.10-3.95 (4H, m), 3.82 (1H, s),3.81 (3H, s), 1.57 (2H, quintet), 1.34 (2H, sextet), 0.89 (3H, t).

Example 2-52 Methyl(3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](2-hydroxyethyl)amino]methyl}phenyl)acetate

(i) 2-{[2-(6-Amino-2-butoxy-8-methoxy-9H-purin-yl)ethyl]amino}ethanol

To the compound obtained by Example 2-39 step (i) (300 mg) inacetonitrile (5 ml) was added 2-aminoethanol (265 mg) and heated at 70°C. for 24 hours. The reaction mixture was purified by columnchromatography (ethyl acetate:7N ammonia-methanol 95:5) to give thetitled compound. Yield: 295 mg (100%).

¹H NMR δ (CDCl₃) 5.20 (2H, s), 4.27 (2H, t), 4.11 (3H, s), 4.05 (2H, t),3.60 (2H, t), 3.03 (2H, t), 2.82 (2H, t), 1.81-1.69 (2H, m), 1.49 (2H,sextet), 0.96 (3H, t).

(ii) Methyl(3-{[[2-(6-amino-2-butoxy-8-methoxy-9H-purin-9-yl)ethyl](2-hydroxyethyl)amino]methyl}phenyl)acetate

A suspension of the compound obtained in the step (i) (270 mg), methyl[3-(bromomethyl)phenyl]acetate (245 mg) and potassium carbonate (140 mg)in acetonitrile (3 ml) was stirred at room temperature for 24 hours. Tothe resultant was added water and the mixture was extracted with ethylacetate. The organic layer was dried and concentrated under reducedpressure and purified by column chromatography (dichloromethane: 7Nammonia-methanol, 95:5) to give the titled compound as a colorlesssolid. Yield: 170 mg (42%); MS APCI+ve 487 (M+H).

¹H NMR δ (CDCl₃) 7.11-7.04 (2H, m), 6.88-6.82 (2H, m), 5.16 (2H, s),4.24 (2H, t), 3.98 (3H, s), 3.95 (2H, t), 3.67 (3H, s), 3.62-3.56 (2H,m), 3.52 (2H, s), 3.51 (2H, s), 3.33-3.27 (1H, m), 2.84 (2H, t), 2.74(2H, t), 1.75 (2H, quintet), 1.48 (2H, sextet), 0.96 (3H, t).

(iii) Methyl(3-{[[2-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)ethyl](2-hydroxyethyl)amino]methyl}phenyl)acetate

Using the compound obtained in the step (ii) (170 mg), the same mannerto Example 2-41 step (iii) was conducted to give the titled compound asa colorless solid. Yield: 150 mg (91%); MS APCI+473 ve (M+H).

¹H NMR δ (DMSO d₆) 9.81 (1H, s), 7.09 (1H, t), 7.03-6.98 (3H, m), 6.36(2H, s), 4.34 (1H, t), 4.05 (2H, t), 3.73 (2H, t), 3.59 (3H, s), 3.57(2H, s), 3.54 (2H, s), 3.39 (2H, q), 2.73, (2H, t), 2.54 (2H, t), 1.58(2H, quintet), 1.35 (2H, sextet), 0.89 (3H, t).

Example 2-53 Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxyethyl)amino]methyl}phenyl)acetate

(i) Methyl (3-{[(2-hydroxyethyl)amino]methyl}phenyl)acetate oxalate

Using 2-aminoethanol (2.5 ml), the same manner to Example 2-46 step (i)was conducted to give the titled compound as a colorless solid. Yield:250 mg (39%).

¹H NMR δ (DMSO d₆) 7.43-7.27 (4H, m), 4.13 (2H, s), 3.70 (2H, s), 3.65(2H, t), 3.62 (3H, s), 2.94 (2H, t).

(ii) Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-hydroxyethyl)amino]methyl}phenyl)acetatefumarate

A suspension of the compound obtained in Example 2-13 step (i) (200 mg),the compound obtained in the step (i) (170 mg) and potassium carbonate(300 mg) in dimethylformamide (5 ml) was stirred at 70° C. overnight,and to the resultant was added water. The mixture was extracted withethyl acetate and the organic layer was dried and concentrated underreduced pressure. The residue was dissolved in methanol (10 ml) and 4Nhydrochloric acid-dioxane (5 ml) was added thereto and the mixture wasstirred at room temperature for 20 hours and concentrated under reducedpressure and purified by RPHPLC. Then the resultant was made intofumarate by using 1N fumaric acid in ethanol to give the titledcompound. Yield: 19 mg (6%); MS APCI+501ve (M+H).

¹H NMR δ (DMSO d₆) 9.86 (1H, s), 7.25-7.09 (4H, m), 6.61 (2H, s), 6.39(2H, s), 4.13 (2H, t), 3.65-3.61 (4H, m), 3.59 (3H, s), 3.56 (2H, s),3.44 (2H, t), 2.49-2.45 (2H, m), 1.63 (4H, quintet), 1.45-1.32 (4H, m),0.90 (3H, t).

Example 3 Synthesis of2-butoxy-8-oxo-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same manner to Example 1.

¹H NMR (DMSO-d₆) δ 9.91 (1H, brs), 7.55 (1H, dd, J=1.7, 7.6 Hz), 7.48(1H, dt, J=1.7, 8.2 Hz), 7.17 (1H, d, J=8.2 Hz), 7.00 (1H, t, J=7.6 Hz),6.41 (2H, brs), 4.35 (2H, t, J=5.7 Hz), 4.09 (2H, t, J=6.6 Hz), 4.05(2H, t, J=5.7 Hz), 3.61 (3H, s), 1.64-1.58 (2H, m), 1.42-1.37 (2H, m),0.89 (3H, t, J=7.4 Hz).

Example 4 Synthesis of2-butoxy-8-oxo-9-[2-(2-methoxycarbonylmethylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Example 1.

¹H NMR (DMSO-d₆) δ 9.89 (1H, brs), 7.19 (1H, dt, J=1.7, 8.1 Hz), 7.11(1H, dd, J=1.5, 7.4 Hz), 6.98 (1H, d, J=7.6 Hz), 6.86 (1H, t, J=7.6 Hz),6.41 (2H, brs), 4.23 (2H, t, J=5.7 Hz), 4.12 (2H, t, J=6.6 Hz), 4.03(2H, t, J=5.7 Hz), 3.47 (2H, s), 3.46 (3H, s), 1.65-1.61 (2H, m),1.41-1.36 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Example 5 Synthesis of2-butoxy-8-oxo-9-[2-(4-methoxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Example 1.

¹H NMR (DMSO-d₆) δ 9.78 (1H, brs), 7.87 (2H, d, J=8.9 Hz), 6.97 (2H, d,J=8.9 Hz), 6.43 (2H, brs), 4.37 (2H, t, J=5.0 Hz), 4.08-4.02 (4H, m),3.80 (2H, s), 1.63-1.58 (2H, m), 1.35-1.30 (2H, m), 0.89 (3H, t, J=7.4Hz).

Example 6 Synthesis of2-butoxy-8-oxo-9-[2-(4-methoxycarbonylmethylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Example 1.

¹H NMR (DMSO-d₆) δ 9.90 (1H, s), 7.14 (2H, d, J=8.7 Hz), 6.84 (2H, d,J=8.7 Hz), 6.42 (2H, brs), 4.24 (2H, t, J=5.8 Hz), 4.12 (2H, t, J=6.6Hz), 4.03 (2H, t, J=5.8 Hz), 3.58 (3H, s), 3.57 (2H, s), 1.65-1.61 (2H,m), 1.39-1.34 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Example 7 Synthesis of2-butoxy-8-oxo-9-{2-[4-(2-methoxycarbonylethyl)phenoxy]ethyl}adenine

To 2-butoxy-8-bromo-9-{2-[4-(2-cyanoethyl)phenoxy]ethyl}adenine (948 mg,2.1 mmol) obtained in Reference Example 16 were added water (20 ml) and5N potassium hydroxide (20 ml) and the mixture was stirred at 95° C. for6 hours. The resultant was adjusted to pH 5 with concentratedhydrochloric acid, and then the precipitated solid was collected byfiltration. Methanol (25 ml) and sulfuric acid (400 μl) were addedthereto, followed by stirring at 90° C. for 4 hours. The reactionsolution was neutralized with saturated sodium hydrogencarbonate, andthe precipitated solid was collected by filtration to give 750 mg (1.7mmol) of the titled compound as a white solid. Yield: 85%.

¹H NMR (DMSO-d₆) δ 9.90 (1H, brs), 7.08 (2H, d, J=8.6 Hz), 6.80 (2H, d,J=8.6 Hz), 6.41 (2H, brs), 4.24 (2H, t, J=5.8 Hz), 4.11 (2H, t, J=6.6Hz), 4.01 (2H, t, J=5.8 Hz), 3.67 (3H, s), 2.76 (2H, t, J=7.6 Hz), 2.55(2H, t, J=7.6 Hz), 1.64-1.59 (2H, m), 1.41-1.36 (2H, m), 0.90 (3H, t,J=7.4 Hz).

Example 8 Synthesis of2-butoxy-8-oxo-9-[4-(3-methoxycarbonylbenzenesulfonamide)butyl]adenine

To2-butoxy-8-methoxy-9-[4-(3-methoxycarbonylbenzenesulfonamide)butyl]adenine(64 mg, 0.13 mmol) obtained in Reference Example 22 were added methanol(10 ml) and sulfuric acid (300 μl), and the mixture was stirred at 85°C. for 3 hours. The mixture was neutralized with saturated sodiumhydrogencarbonate, diluted with water and the precipitated solid wascollected by filtration to give 54 mg (0.11 mmol) of the titled compoundas a white solid. Yield: 87%.

¹H NMR (DMSO-d₆) δ 9.82 (1H, s), 8.30 (1H, dd, J=1.4, 1.7 Hz), 8.17 (1H,ddd, J=1.3, 1.4, 7.9 Hz), 8.01 (1H, ddd, J=1.3, 1.7, 7.9), 7.78 (1H, t,J=5.8 Hz), 7.72 (1H, t, J=7.9 Hz), 6.49 (2H, brs), 4.11 (2H, t, J=6.6Hz), 3.89 (3H, s), 3.58 (2H, t, J=6.7 Hz), 2.77 (2H, dt, J=5.8, 6.6 Hz),1.64-1.59 (4H, m), 1.41-1.36 (2H, m), 1.33-1.28 (2H, m), 0.89 (3H, t,J=7.4 Hz).

Example 9 Synthesis of2-butoxy-8-oxo-9-[4-(3-methoxycarbonylmethylbenzenesulfonamide)butyl]adenine

To2-butoxy-8-oxo-9-[4-(3-hydroxycarbonylmethylbenzenesulfonamide)butyl]adenine(100 mg, 0.2 mmol) obtained in Comparison Example 9 were added methanol(15 ml) and sulfuric acid (200 μl) and the mixture was stirred at 80° C.for 3 hours. The mixture was and neutralized with an aqueous ammoniumsolution, and water was added thereto. Precipitated solid was collectedby filtration to give 89 mg (0.2 mmol) of the titled compound, as awhite solid. Yield: 91%.

¹H NMR (DMSO-d₆) δ 9.82 (1H, s), 7.68 (1H, s), 7.66-7.64 (1H, m), 7.59(1H, t, J=5.8 Hz), 7.52-7.50 (1H, m), 6.40 (2H, brs), 4.12 (2H, t, J=6.6Hz), 3.81 (3H, s), 3.59 (2H, t, J=6.6 Hz), 2.75 (2H, dt, J=5.8, 6.6 Hz),1.65-1.58 (4H, m), 1.40-1.34 (2H, m), 1.36-1.29 (2H, m), 0.91 (3H, t,J=7.4 Hz).

Example 10 Synthesis of2-butoxy-8-oxo-9-[4-(3-methoxycarbonylphenylaminocarbonylamino)butyl]adenine

The titled compound was obtained by the same method as Example 8.

¹H NMR (DMSO-d₆) δ 9.85 (1H, brs), 8.67 (1H, s), 8.10 (1H, dd, J=1.5,2.2 Hz), 7.56 (1H, ddd, J=1.0, 2.2, 8.2 Hz), 7.47 (1H, ddd, J=1.0, 1.5,7.6 Hz), 7.34 (1H, dd, J=7.6, 8.2 Hz), 6.40 (2H, brs), 6.17 (1H, t,J=5.7 Hz), 4.13 (2H, t, J=6.6 Hz), 3.83 (3H, s), 3.67 (2H, t, J=6.8 Hz),3.10 (2H, dt, J=5.7, 6.6 Hz), 1.69-1.63 (2H, m), 1.64-1.59 (2H, m),1.44-1.37 (2H, m), 1.40-1.35 (2H, m), 0.88 (3H, t, J=7.4 Hz).

Example 11 Synthesis of2-butoxy-8-oxo-9-[4-(3-methoxycarbonylmethylphenylaminocarbonylamino)butyl]adenine

To a solution of2-butoxy-8-methoxy-9-[4-(3-hydroxymethylphenylaminocarbonylamino)butyl]adenine(300 mg, 0.66 mmol) obtained in Reference Example 27 in chloroform (7ml) were added under ice-cooling triethylamine (1.08 ml, 7.86 mmol) andthionyl chloride (143 μl, 3.94 mmol), and the mixture was stirred for 5minutes. Saturated sodium hydrogencarbonate was added thereto, and themixture was diluted with water and extracted with chloroform (methanol5%). The organic layer was washed with water and saturated brine, driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was dissolved in DMF 10 ml, and sodium cyanide 96 mg (2.0 mmol)was added thereto at room temperature, followed by stirring at roomtemperature for 22 hours. To the reaction mixture was added saturatedammonium chloride, and the mixture was concentrated under reducedpressure. To the residue was added water and the mixture was extractedwith chloroform (methanol 5%). The organic layer was washed withsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. To the residue were added methanol (5 ml) and 5Npotassium hydroxide (5 ml), followed by stirring at 90° C. for 6.5hours. The resultant was neutralized with concentrated hydrochloric acidand concentrated under reduced pressure. To the residues were addedmethanol (20 ml) and the mixture was concentrated sulfuric acid (0.3ml), followed by stirring at 90° C. for 2 hours. After cooling, theresultant was neutralized with an aqueous ammonium solution, and theprecipitated solid was collected by filtration to give 140 mg (0.29mmol) of the titled compound as a white solid. Yield: 44%.

¹H NMR (DMSO-d₆) δ 9.85 (1H, s), 8.39 (1H, s), 7.34 (1H, s), 7.26 (1H,d, J=8.2 Hz), 7.14 (1H, dd, J=7.5, 8.2 Hz), 6.76 (1H, d, J=7.5 Hz), 6.40(2H, brs), 6.10 (1H, t, J=5.7 Hz), 4.13 (2H, t, J=6.6 Hz), 3.60 (3H, s),3.58 (2H, s), 3.08 (2H, dt, J=5.7, 6.6 Hz), 1.68-1.60 (4H, m), 1.40-1.32(4H, m), 0.89 (3H, t, J=7.4 Hz).

Example 12 Interferon Inducing Activity of Rat Spleen Cells (In Vitro)

Spleen was removed from CD(SD)IGS rat (male; 8-10 weeks old). Asuspension of spleen cells of 1×10⁷ cells/ml was prepared by using nonserum MEN broth, and each 0.1 ml thereof was poured in a well of 96-wellmicroplate. The test sample diluted with the broth (containing 0.2%DMSO) in each 0.1 ml was poured in the well and incubated in 5% CO₂incubator at 37° C. for 24 hours. The culture broth was centrifuged togive a supernatant of the incubation. The interferon activity in thesupernatant of the broth was quantitatively measured by thepartially-improved bioassay method described in A. Armstrong, Methods inEnzymology 78, 381-7. Namely after mouse fibroblast L929 in 4×10⁴cells/50 μl was cultured in a 96-well culture plate for 7 hour, theretowas added 50 μl of the diluted culture supernatant and the mixture wasfurther cultured for 17 hours. After the cultured broth in each well wasremoved, each 100 μl of vesicular stomatitis virus was added to eachwell and the effect of the cell denaturation 44 hours after the virusinfection was confirmed by the neutral red stain. In Table 30, aninterferon inducing activity (minimum effective concentration) on eachcompound was shown.

TABLE 30 Minimum effective Compound concentration (nM) Example 1 0.3Example 2 3 Example 3 1 Example 4 1 Example 6 10 Example 8 3 Example 9 3Example 10 1 Example 11 10 Comparison Example 1 10 Comparison Example 230 Comparison Example 3 100 Comparison Example 4 100 Comparison Example6 100 Comparison Example 8 100 Comparison Example 9 300 ComparisonExample 10 300 Comparison Example 11 100

Example 13 Metabolic Stability Test Using Human Plasma

Plasma was prepared from fresh human blood and the test compound(containing 1% DMSO) of the final concentration of 1 μM was addedthereto.

After a metabolic reaction by plasma esterase was conducted at 37° C.for 15 minutes, the test compound was extracted with ethyl acetate, andquantitatively analyzed by reverse phase HPLC. The metabolic stabilityof the test compound was shown by the residual amount (%) per theconcentration of pre-metabolization as 100%. The result was shown inTable 31.

TABLE 31 Compound Residual rate (%) Example 2 1.4 Example 9 <1.0

Example 14 Metabolic Stability Test on Rat Liver S9

The reaction using liver S9 of rat was conducted on a 96-well plate byusing a screening robot by Tecan Company. S9 solution was prepared byadding 250 mM Kpi (ph 7.4) 20 ml and deionized water 20 ml to 10 ml ofliver S9 of rat, a Cofactor solution was prepared by dissolving NADPH220 mg in deionized water 40.5 ml (Final 6 mM), and IS (InternalStandard) solution was prepared by adding IS solution (1 mM DMSOsolution) 300 μl to acetonitrile 30 ml (100 times dilution). The testcompound (1 μM DMSO solution) was dissolved in an incubator at 37° C.After each 35 μL was poured in a 96-well plate (24 samples/plate),plates (sample plates, 96-well plates for dilution, each Deep wellplates for the reaction and the recovery, plates for extraction of asolid phase) and reagents (S9 solution, Cofactor solution, IS (InternalStandard) solution, Stop solution, acetonitrile for elution) were set tothe specified position in the booth of the robot and the reactionstarted (the concentration of the test compounds was 1 μM). Incubationwas conducted under shaking at 37° C., the solid phase was extracted (atthe same time, the internal standard for analysis was added). To therecovered samples 200 μL/well was added 50 μL of acetonitrile per eachwell, and to 2 plates of FALCON Deep well were poured 100 μL/well of thesolution per well. By subjecting to the LC/MS analysis, thechromatography of the test compound and the internal standard weredescribed and the peak area was calculated. And then, the stability(residual rate after reaction) was calculated. The result was shown inTable 32.

TABLE 32 Compound Residual rate (%) Example 1 0 Example 2 1 Example 3 0Example 4 0 Example 5 0 Example 6 0 Example 7 0 Example 8 0 Example 9 0Example 10 1

Comparison Example 1 Synthesis of2-butoxy-8-oxo-9-[2-(3-hydroxycarbonylphenoxy)ethyl]adenine

To 2-butoxy-8-oxo-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (50 mg,0.12 mmol) obtained in Example 1 were added methanol (2.5 ml) and 2.5Npotassium hydroxide (5 m), and the mixture was stirred at 85° C. for 4.5hours. After cooling, water was added and the resultant was made to pH 5by concentrated hydrochloric acid. The precipitated crystal wascollected by filtration to give 49 mg (0.12 mmol) of the titled compoundas a white solid. Yield: 100%.

¹H NMR (DMSO-d₆) δ 13.02 (1H, br), 10.23 (1H, brs), 7.51 (1H, dd, J=1.2,8.8 Hz), 7.38-7.36 (2H, m), 7.14 (1H, dd, J=0.8, 2.6 Hz), 6.57 (2H,brs), 4.32 (2H, t, J=5.7 Hz), 4.11-4.04 (4H, m), 1.65-1.60 (2H, m),1.40-1.35 (2H, m), 0.89 (3H, t, J=7.4 Hz).

Comparison Example 2 Synthesis of2-butoxy-8-oxo-9-[2-(3-hydroxycarbonylmethylphenoxy)ethyl]adenine)

From 2-butoxy-8-oxo-9-[2-(3-methoxycarbonylmethylphenoxy)ethyl]adenine15 mg (0.04 mmol) obtained in Example 2, 10 mg (0.03 mmol) of the titledcompound was obtained as a white solid by the same method as ComparisonExample 1. Yield: 70%.

¹H NMR (DMSO-d₆) δ 12.43 (1H, br), 9.93 (1H, s), 7.22-7.20 (1H, m),6.81-7.78 (3H, m), 6.45 (2H, br), 4.24 (2H, t, J=5.8 Hz), 4.12 (2H, t,J=6.6 Hz), 4.04 (2H, t, J=5.8 Hz), 3.50 (2H, s), 1.65-1.60 (2H, m),1.39-1.35 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Comparison Example 3 Synthesis of2-butoxy-8-oxo-9-[2-(2-hydroxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.46 (1H, br), 10.03 (1H, brs), 7.61 (1H, dd, J=1.7,7.6 Hz), 7.45 (1H, dt, J=1.7, 8.2 Hz), 7.16 (1H, d, J=8.2 Hz), 7.00 (1H,t, J=7.6 Hz), 6.49 (2H, brs), 4.33 (2H, t, J=5.7 Hz), 4.09 (2H, t, J=6.6Hz), 4.04 (2H, t, J=5.7 Hz), 1.64-1.59 (2H, m), 1.39-1.34 (2H, m), 0.89(3H, t, J=7.4 Hz).

Comparison Example 4 Synthesis of2-butoxy-8-oxo-9-[2-(2-hydroxycarbonylmethylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.17 (1H, br), 10.35 (1H, br), 7.16-7.14 (1H, m),6.97 (1H, d, J=7.6 Hz), 6.86 (1H, d, J=7.6 Hz), 6.58 (2H, brs), 4.21(2H, t, J=5.7 Hz), 4.11 (2H, t, J=6.6 Hz), 4.02 (2H, t, J=5.7 Hz), 3.40(2H, s), 1.65-1.60 (2H, m), 1.39-1.35 (2H, m), 0.88 (3H, t, J=7.4 Hz).

Comparison Example 5 Synthesis of2-butoxy-8-oxo-9-[2-(4-hydroxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.62 (1H, br), 9.47 (1H, brs), 7.84 (2H, d, J=8.7Hz), 6.97 (2H, d, J=8.7 Hz), 6.35 (2H, brs), 4.36 (2H, t, J=5.0 Hz),4.11-4.08 (4H, m), 1.65-1.60 (2H, m), 1.37-1.32 (2H, m), 0.90 (3H, t,J=7.4 Hz).

Comparison Example 6 Synthesis of2-butoxy-8-oxo-9-[2-(4-methoxycarbonylmethylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.25 (2H, br), 9.97 (1H, br), 7.12 (2H, d, J=8.7Hz), 6.83 (2H, d, J=8.7 Hz), 6.44 (2H, brs), 4.24 (2H, t, J=5.8 Hz),4.12 (2H, t, J=6.6 Hz), 4.03 (2H, t, J=5.8 Hz), 3.45 (2H, s), 1.65-1.60(2H, m), 1.40-1.35 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Comparison Example 7 Synthesis of2-butoxy-8-oxo-9-{2-[4-(2-hydroxycarbonylethyl)phenoxy]ethyl}adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.12 (1H, br), 10.03 (1H, brs), 7.09 (2H, d, J=8.6Hz), 6.79 (2H, d, J=8.6 Hz), 6.47 (2H, brs), 4.22 (2H, t, J=5.8 Hz),4.11 (2H, t, J=6.6 Hz), 4.04 (2H, t, J=5.8 Hz), 2.72 (2H, t, J=7.6 Hz),2.43 (2H, t, J=7.6 Hz), 1.64-1.59 (2H, m), 1.41-1.36 (2H, m), 0.90 (3H,t, J=7.4 Hz).

Comparison Example 8 Synthesis of2-butoxy-8-oxo-9-[4-(3-hydroxycarbonylbenzenesulfonamide)butyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 13.59 (1H, br), 10.06 (1H, brs), 8.29 (1H, dd, J=1.4,1.7 Hz), 8.13 (1H, ddd, J=1.3, 1.4, 7.9 Hz), 7.92 (1H, ddd, J=1.3, 1.7,7.9 Hz), 7.71 (1H, t, J=5.8 Hz), 7.66 (1H, t, J=7.9 Hz), 6.47 (2H, brs),4.11 (2H, t, J=6.6 Hz), 3.60 (2H, t, J=6.6 Hz), 2.75 (2H, dt, J=5.8, 6.6Hz), 1.63-1.58 (4H, m), 1.38-1.32 (4H, m), 0.89 (3H, t, J=7.4 Hz).

Comparison Example 9 Synthesis of2-butoxy-8-oxo-9-[4-(3-hydroxycarbonylmethylbenzenesulfonamide)butyl]adenine

To2-butoxy-8-methoxy-9-[4-(3-cyanomethylbenzenesulfonamide)butyl]adenine(190 mg, 0.4 mmol) obtained in Reference Example 25 were added methanol(3 ml) and 3.7N potassium hydroxide (3 ml) and the mixture was stirredat 90° C. for 3 hours. The resultant was adjusted to pH 5 by 1Nhydrochloric acid, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in 1N sodium hydroxide andwashed with chloroform. The aqueous layer was adjusted to pH 5 with 1Naqueous hydrochloric acid solution, and the precipitated solid wascollected by filtration to give 145 mg (0.3 mmol) of the titled compoundas a white solid. Yield: 73%.

¹H NMR (DMSO-d₆) δ 12.48 (1H, brs), 9.98 (1H, s), 7.68 (1H, s),7.64-7.62 (1H, m), 7.58 (1H, t, J=5.9 Hz), 7.50-7.48 (1H, m), 7.48 (1H,d, J=1.0 Hz), 6.48 (2H, brs), 4.12 (2H, t, J=6.6 Hz), 3.69 (2H, brs),3.59 (2H, t, J=6.6 Hz), 2.75 (2H, dt, J=5.9, 6.6 Hz), 1.65-1.58 (4H, m),1.40-1.36 (2H, m), 1.35-1.29 (2H, m), 0.91 (3H, t, J=7.4 Hz).

Comparison Example 10 Synthesis of2-butoxy-8-oxo-9-[4-(3-hydroxycarbonylphenylaminocarbonylamino)butyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.82 (1H, brs), 9.86 (1H, s), 8.61 (1H, s), 8.01(1H, dd, J=1.5, 2.2 Hz), 7.57 (1H, ddd, J=1.0, 2.2, 8.2 Hz), 7.45 (1H,ddd, J=1.0, 1.5, 7.6 Hz), 7.31 (1H, dd, J=7.6, 8.2 Hz), 6.41 (2H, brs),6.16 (1H, t, J=5.7 Hz), 4.13 (2H, t, J=6.6 Hz), 3.68 (2H, t, J=6.8 Hz),3.10 (2H, dt, J=5.7, 6.6 Hz), 1.70-1.64 (2H, m), 1.64-1.59 (2H, m),1.44-1.37 (2H, m), 1.39-1.33 (2H, m), 0.88 (3H, t, J=7.4 Hz).

Comparison Example 11 Synthesis of2-butoxy-8-oxo-9-[4-(3-hydroxycarbonylmethylphenylaminocarbonylamino)butyl]adenine

The titled compound was obtained by the same method as ComparisonExample 1.

¹H NMR (DMSO-d₆) δ 12.29 (1H, br), 9.90 (1H, s), 8.38 (1H, s), 7.28 (1H,s), 7.25 (1H, d, J=8.2 Hz), 7.13 (1H, dd, J=7.5, 8.2 Hz), 6.76 (1H, d,J=7.5 Hz), 6.41 (2H, brs), 6.10 (1H, t, J=5.7 Hz), 4.14 (2H, t, J=6.6Hz), 3.68 (2H, t, J=6.8 Hz), 3.46 (2H, s), 3.08 (2H, dt, J=5.7, 6.6 Hz),1.68-1.59 (4H, m), 1.42-1.35 (4H, m), 0.89 (3H, t, J=7.4 Hz).

Reference Example 1 Synthesis of methyl 3-(2-bromoethoxy)benzoate

To a solution of methyl 3-hydroxybenzoate (2.00 g, 13.1 mmol) in acetone(50 ml) were added potassium carbonate (3.18 g, 23.0 mmol) and1,2-dibromoethane (6.4 ml, 74.1 mmol) and the mixture was stirred at 85°C. for 24 hours. After cooling, the resultant was concentrated underreduced pressure. To the residue was added 75 ml of water and themixture was extracted with ethyl acetate. The organic layer was washedwith 1N aqueous sodium hydroxide solution, water and saturated brine inthis order, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give 1.79 g (6.9 mmol) of the titled compound as an yellow oil.Yield: 53%.

¹H NMR (CDCl₃) δ 7.67 (1H, dt, J=1.5, 7.8 Hz), 7.56 (1H, dd, J=1.5, 2.6Hz), 7.36 (1H, t, J=7.8 Hz), 7.15-7.13 (1H, m), 4.34 (2H, t, J=6.2 Hz),3.92 (3H, s), 3.66 (2H, t, J=6.2 Hz).

Reference Example 2 Synthesis of2-butoxy-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine

To 2-butoxyadenine (727 mg, 3.5 mmol) and potassium carbonate (727 mg,5.3 mmol) was added DMF (35 ml), and the mixture was stirred at 70° C.for 2 hours. Then a solution of methyl 3-(2-bromoethoxy)benzoateobtained in Reference Example 1 (1.0 g, 3.9 mmol) in DMF (2 ml) wasadded thereto under ice-cooling, followed by stirring at roomtemperature for 3 hours. The solvent was removed under reduced pressure,and to the residue was added water. The mixture was neutralized withconcentrated hydrochloric acid and extracted with chloroform (methanol5%). The organic layer was washed with water and saturated brine, driedover sodium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give, as whitecrystal, 1.1 g (2.9 mmol) of the titled compound. Yield: 81%.

¹H NMR (CDCl₃) δ 7.83 (1H, s), 7.65 (1H, dt, J=1.5, 8.0 Hz), 7.51 (1H,dd, J=1.5, 2.6 Hz), 7.31 (1H, t, J=8.0 Hz), 7.07 (1H, ddd, J=0.9, 2.6,8.0 Hz), 5.88 (2H, br), 4.53 (2H, t, J=4.8 Hz), 4.33 (4H, m), 3.90 (3H,s), 1.83-1.73 (2H, m), 1.53-1.47 (2H, m), 0.97 (3H, t, J=7.4 Hz).

Reference Example 3 Synthesis of2-butoxy-9-[2-(3-methoxycarbonylmethylphenoxy)ethyl]adenine

To a suspension of lithium aluminum hydride (150 mg, 4.0 mmol) in THF(15 ml) was added a solution of2-butoxy-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (540 mg, 1.4 mmol)obtained in Reference Example 2 in THF (5 ml) under ice-cooling, and themixture was stirred at room temperature for 3 hours. 1N Aqueous sodiumhydroxide solution was added thereto, followed by filtration throughcelite pad and concentration under reduced pressure. The residue wasdissolved in chloroform (10 ml), and thionyl chloride (336 μl, 4.62mmol) was added thereto at room temperature, followed by stirring at 60°C. for 10 minutes. To the reaction mixture was added 1N aqueous sodiumhydroxide solution, and the mixture was diluted with water and extractedwith chloroform (methanol 5%). The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated under reducedpressure to give chloromethyl product as a pale yellow crystal, 380 mg.To a solution of the chloromethyl product (380 mg) in DMF (10 ml) wasadded sodium cyanide (99 mg, 2.02 mmol) at room temperature, followed bystirring at room temperature for 1 hour. To the reaction mixture wasadded saturated ammonium chloride and the mixture was concentrated underreduced pressure. To the residue was added water and the mixture wasextracted with chloroform (methanol 5%). The organic layer was washedwith water and saturated brine, dried over sodium sulfate andconcentrated under reduced pressure. To the residue were added methanol(7 ml) and 5N aqueous potassium hydroxide solution (7 ml) and themixture was stirred at 95° C. for 3.5 hours. The reaction solution wasneutralized with concentrated hydrochloric acid, and concentrated underreduced pressure. Methanol (20 ml) and concentrated sulfuric acid (0.3ml) were added thereto, followed by stirring at 90° C. for 3.5 hours.After cooling, the resultant was concentrated under reduced pressure,and to the residue was added water. The solution was extracted withchloroform (methanol 5%). The organic layer was washed with water andsaturated brine, dried over sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give 160 mg (0.40 mmol) of the titled compound as apale yellow oil. Yield: 29%.

¹H NMR (DMSO-d₆) δ 7.22 (1H, t, J=7.8 Hz), 6.87 (1H, d, J=7.8 Hz),6.80-6.77 (2H, m), 5.51 (2H, brs), 4.56 (2H, t, J=4.8 Hz), 4.31-4.27(4H, m), 3.68 (3H, s), 3.58 (2H, s), 1.82-1.78 (2H, m), 1.53-1.48 (2H,m), 0.97 (3H, t, J=7.4 Hz).

Reference Example 4 Synthesis of methyl 2-(2-bromoehyoxy)benzoate

The titled compound was obtained by the same method as Reference Example1.

¹H NMR (CDCl₃) δ 7.60 (1H, dd, J=1.6, 7.6 Hz), 7.46-7.44 (1H, m),7.04-7.02 (1H, m), 6.97 (1H, dt, 0.6, 8.3 Hz), 4.36 (2H, t, J=6.5 Hz),3.90 (3H, s), 3.68 (2H, t, J=6.5 Hz).

Reference Example 5 Synthesis of2-butoxy-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Reference Example2.

¹H NMR (DMSO-d₆) δ 8.01 (1H, s), 7.64 (1H, dd, J=1.8, 7.7 Hz), 7.51-7.50(1H, m), 7.19 (2H, brs), 7.15 (1H, d, J=8.1 Hz), 7.02-7.00 (1H, m),4.47-4.42 (2H, m), 4.38-4.34 (2H, m), 4.18 (2H, t, J=6.6 Hz), 3.73 (3H,s), 1.67-1.76 (2H, m), 1.41-1.38 (2H, m), 0.89 (3H, t, J=7.4 Hz).

Reference Example 6 Synthesis of2-butoxy-9-[2-(2-hydroxymethylphenoxy)ethyl]adenine

To a suspension of lithium aluminum hydride (74 mg, 1.9 mmol) in THF (10ml) was added a solution of2-butoxy-9-[2-(2-methoxycarbonylphenoxy)ethyl]adenine (500 mg, 1.4 mmol)obtained by Reference Example 5 in THF (2 ml) under ice-cooling, and themixture was stirred at room temperature for 1 hour. 1N Aqueous sodiumhydroxide solution was added thereto, followed by filtration throughcelite pad, and the filtrate was concentrated under reduced pressure togive 500 mg (1.4 mmol) of the titled compound as a white solid. Yield:99%.

¹H NMR (DMSO-d₆) δ 7.98 (1H, s), 7.32 (1H, d, J=7.6 Hz), 7.18 (2H, brs),7.15-7.13 (1H, m), 6.94-6.92 (1H, m), 6.91-6.89 (1H, m), 4.96 (1H, t,4.9 Hz), 4.44 (2H, t, J=5.1 Hz), 4.33 (2H, d, J=4.9 Hz), 4.29 (2H, t,J=5.1 Hz), 4.19 (2H, t, J=6.6 Hz), 1.67-1.62 (2H, m), 1.41-1.37 (2H, m),0.92 (3H, t, J=7.4 Hz).

Reference Example 7 Synthesis of2-butoxy-9-[2-(2-chloromethylphenoxy)ethyl]adenine

To a solution of 2-butoxy-9-[2-(2-hydroxymethylphenoxy)ethyl]adenine(500 ml, 1.4 mmol) obtained in Reference Example 6 in chloroform (10 ml)was added thionyl chloride (510 μl, 7.0 mmol) at room temperature, andthe mixture was stirred at 60° C. for 1 hour. 1N Aqueous sodiumhydroxide solution was added to the resultant, followed by dilution withwater and extraction with chloroform (methanol 5%). The organic layerwas washed with water and saturated brine, dried over sodium sulfate andconcentrated under reduced pressure to give 529 mg (1.3 mmol) of thetitled compound as a pale yellow solid. Yield: 93%.

¹H NMR (DMSO-d₆) δ 8.07 (1H, s), 7.33-7.31 (4H, m), 7.04 (1H, d, J=8.1Hz), 6.93 (1H, t, J=7.2 Hz), 4.59 (2H, s), 4.50-4.48 (2H, m), 4.38-4.36(2H, m), 4.21 (2H, t, J=6.6 Hz), 1.69-1.64 (2H, m), 1.45-1.40 (2H, m),0.92 (3H, t, J=7.4 Hz).

Reference Example 8 Synthesis of2-butoxy-9-[2-(2-cyanomethylphenoxy)ethyl]adenine

To a solution of 2-butoxy-9-[2-(2-chloromethylphenoxy)ethyl]adenine (529mg, 1.3 mmol) obtained in Reference Example 7 in DMF (14 ml) was addedsodium cyanide (207 mg, 4.2 mmol) at room temperature and the mixturewas stirred at room temperature for 1 hour. Saturated ammonium chloridewas added thereto and concentrated under reduced pressure. To theresidue was added water and the solution was extracted with chloroform(methanol 5%). The organic layer was washed with water and an aqueoussaline solution, dried over sodium sulfate and concentrated underreduced pressure to give 436 mg (1.2 mmol) of the titled compound aspale a yellow solid. Yield: 84%.

¹H NMR (DMSO-d₆) δ 8.32 (1H, s), 7.32-7.30 (2H, m), 7.20 (2H, br), 7.06(1H, d, J=8.0 Hz), 7.97 (1H, t, J=7.1 Hz), 4.47 (2H, t, J=5.0 Hz), 4.36(2H, t, J=5.0 Hz), 4.19 (2H, t, J=6.6 Hz), 3.73 (2H, s), 1.69-1.64 (2H,m), 1.45-1.40 (2H, m), 0.92 (3H, t, J=7.4 Hz).

Reference Example 9 Synthesis of2-butoxy-9-[2-(2-methoxycarbonylmethylphenoxy)ethyl]adenine

To 2-butoxy-9-[2-(2-cyanomethylphenoxy)ethyl]adenine (436 mg, 1.2 mmol)obtained in Reference Example 8 were added methanol (12 ml) and 5Naqueous potassium hydroxide solution (12 ml), and the mixture was heatedat 95° C. for 6.5 hours. The reaction solution was neutralized withconcentrated hydrochloric acid and the precipitated solid was collectedby filtration. Methanol (15 ml) and concentrated sulfuric acid (0.3 ml)were added thereto and the mixture was stirred at 75° C. for 5 hours.After cooling, the resultant was neutralized with saturated sodiumhydrogencarbonate solution, and methanol was removed by distillation.The precipitated solid was collected by filtration to give 384 mg (1.0mmol) of the titled compound as a white solid. Yield: 81%.

¹H NMR (DMSO-d₆) δ 8.01 (1H, s), 7.22-7.20 (3H, m), 7.14 (1H, dd, J=1.6,7.4 Hz), 6.98 (1H, d, J=6.5 Hz), 6.88 (1H, dt, J=0.8, 7.4 Hz), 4.41 (2H,t, J=5.0 Hz), 4.28 (2H, t, J=5.0 Hz), 4.19 (2H, t, J=6.6 Hz), 3.53 (3H,s), 3.50 (2H, s), 1.69-1.64 (2H, m), 1.42-1.37 (2H, m), 0.90 (3H, t,J=7.4 Hz).

Reference Example 10 Synthesis of methyl 4-(2-bromoethoxy)benzoate

The titled compound was obtained by the same method as Reference Example1.

¹H NMR (CDCl₃) δ 7.99 (2H, d, J=9.0 Hz), 6.92 (2H, d, J=9.0), 4.35 (2H,t, J=6.2 Hz), 3.89 (3H, s), 3.66 (2H, t, J=6.2 Hz).

Reference Example 11 Synthesis of2-butoxy-9-[2-(4-methoxycarbonylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Reference Example2.

¹H NMR (DMSO-d₆) δ 7.97 (2H, d, J=8.6 Hz), 7.27 (1H, s), 6.90 (2H, d,J=8.6 Hz), 5.84 (2H, brs), 4.54 (2H, m), 4.38-4.34 (2H, m), 4.18 (2H, t,J=6.6 Hz), 3.73 (3H, s), 1.67-1.76 (2H, m), 1.41-1.38 (2H, m), 0.89 (3H,t, J=7.4 Hz).

Reference Example 12 Synthesis of methyl 4-(2-bromoethoxy)phenylacetate

The titled compound was obtained by the same method as Reference Example1.

¹H NMR (CDCl₃) δ 7.21 (2H, d, J=8.7 Hz), 6.88 (2H, d, J=8.7 Hz), 4.30(2H, t, J=6.3 Hz), 3.71 (3H, s), 3.65 (2H, t, J=6.3 Hz), 3.59 (2H, s).

Reference Example 13 Synthesis of2-butoxy-9-[2-(4-methoxycarbonylmethylphenoxy)ethyl]adenine

The titled compound was obtained by the same method as Reference Example2.

¹H NMR (DMSO-d₆) δ 7.96 (1H, s), 7.18 (2H, brs), 7.14 (2H, d, J=8.7 Hz),6.86 (2H, d, J=8.7 Hz), 4.42 (2H, t, J=5.4 Hz), 4.32 (2H, t, J=5.4 Hz),4.19 (2H, t, J=6.6 Hz), 3.58 (5H, s), 1.68-1.63 (2H, m), 1.41-1.36 (2H,m), 0.91 (3H, t, J=7.4 Hz).

Reference Example 14 Synthesis of2-butoxy-9-{2-[4-(2-hydroxyethyl)phenoxy]ethyl}adenine

The titled compound was obtained by the same method as Reference Example6.

¹H NMR (DMSO-d₆) δ 7.95 (1H, s), 7.18 (2H, brs), 7.08 (2H, d, J=8.6 Hz),6.81 (2H, d, J=8.6 Hz), 4.58 (2H, t, J=5.3 Hz), 4.40 (2H, t, J=5.2 Hz),4.29 (2H, t, J=5.2 Hz), 4.19 (2H, t, J=6.6 Hz), 3.51 (2H, dt, J=5.3, 7.2Hz), 2.62 (2H, t, J=7.2 Hz), 1.67-1.62 (2H, m), 1.40-1.35 (2H, m), 0.91(3H, t, J=7.4 Hz).

Reference Example 15 Synthesis of2-butoxy-9-{2-[4-(2-chloroethyl)phenoxy]ethyl}adenine

The titled compound was obtained by the same method as Reference Example7.

¹H NMR (DMSO-d₆) δ 8.05 (1H, s), 7.43 (2H, br), 7.16 (2H, d, J=8.6 Hz),6.87 (2H, d, J=8.6 Hz), 4.43 (2H, t, J=5.2 Hz), 4.32 (2H, t, J=5.2 Hz),4.23 (2H, t, J=6.6 Hz), 3.77 (2H, t, J=7.1 Hz), 2.93 (2H, t, J=7.1 Hz),1.69-1.64 (2H, m), 1.43-1.38 (2H, m), 0.90 (3H, t, J=7.4 Hz).

Reference Example 16 Synthesis of2-butoxy-8-bromo-9-{2-[4-(2-cyanoethyl)phenoxy]ethyl}adenine

To a solution of 2-butoxy-9-{2-[4-(2-chloroethyl)phenoxy]ethyl}adenine(985 mg, 2.6 mmol) obtained in Reference Example 15 in DMF (20 ml) wasadded sodium cyanide (3085 mg, 7.9 mmol) at room temperature, and themixture was stirred at room temperature for 18 hours and at 50° C. for 2hours. 1N Hydrochloric acid was added to the resultant and the mixturewas concentrated under educed pressure. To the residue was added waterand the mixture was extracted with chloroform (methanol 5%). The organiclayer was washed with water and saturated brine, dried over sodiumsulfate and concentrated under reduced pressure to give a cyano product.To a solution of the obtained cyano product in chloroform (25 ml) wereadded sodium acetate (653 mg, 3.6 mmol) and bromine (180 μl, 3.6 mmol)under ice-cooling, followed by stirring at room temperature for 3 hours.Saturated sodium hydrogencarbonate and saturated sodium thiosulfate wereadded to the resultant, followed by stirring for 10 minutes. Thereaction solution was diluted with water and extracted with chloroform(methanol 5%). The organic layer was washed with water and saturatedbrine, dried over sodium sulfate and concentrated under reducedpressure. The resulting crude crystal was recrystallized from methanolto give 948 mg (2.1 mmol) of the titled compound as a pale yellowishwhite solid. Yield: 82%.

¹H NMR (DMSO-d₆) δ 7.11 (2H, d, J=8.6 Hz), 6.81 (2H, d, J=8.6 Hz), 5.46(2H, br), 4.53 (2H, t, J=5.7 Hz), 4.31 (2H, t, J=5.7 Hz), 4.30 (2H, t,J=6.6 Hz), 2.89 (2H, t, J=7.3 Hz), 2.56 (2H, t, J=7.3 Hz), 1.81-1.76(2H, m), 1.52-1.47 (2H, m), 0.97 (3H, t, J=7.4 Hz).

Reference Example 17 Synthesis of(2-butoxy-9-(4-phthalimidobutyl)adenine

The titled compound was obtained by the same method as Reference Example2.

¹H NMR (DMSO-d₆) δ 7.90 (1H, s), 7.85-7.84 (4H, m), 7.14 (2H, brs), 4.14(2H, t, J=6.6 Hz), 4.05 (2H, t, J=7.8 Hz), 3.60 (2H, t, J=6.9 Hz),1.79-1.72 (2H, m), 1.65-1.60 (2H, m), 1.58-1.52 (2H, m), 0.89 (3H, t,J=7.4 Hz).

Reference Example 18 Synthesis of(2-butoxy-8-bromo-9-(4-phthalimidobutyl)adenine

To a solution of 2-butoxy-9-(4-phthalimide butyl)adenine (500 mg, 1.2mmol) obtained in Reference Example 17 in chloroform (13 ml) were addedsodium acetate (334 mg, 1.8 mmol) and bromine (92 μl, 1.8 mmol) underice-cooling, and the mixture was stirred for 2 hours. Saturated sodiumhydrogencarbonate and saturated sodium thiosulfate were added to theresultant, followed by stirring for 10 minutes. The reaction solutionwas diluted with water and extracted with chloroform (methanol 5%). Theorganic layer was washed with water and saturated brine, dried oversodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography to give, as a pale yellowsolid, 575 mg (1.2 mmol) of the titled compound. Yield: 96%.

¹H NMR (DMSO-d₆) δ 7.84-7.82 (4H, m), 7.35 (2H, brs), 4.14 (2H, t, J=6.6Hz), 4.04 (2H, t, J=6.6 Hz), 3.60 (2H, t, J=6.7 Hz), 1.79-1.75 (2H, m),1.60-1.55 (2H, m), 1.37-1.32 (2H, m), 0.88 (3H, t, J=7.4 Hz).

Reference Example 19 Synthesis of2-butoxy-8-methoxy-9-[4-(2-hydroxycarbonylbenzamide)butyl]adenine

To 2-butoxy-8-bromo-9-(4-phthalimidebutyl)adenine (258 mg, 0.53 mmol)obtained in Reference Example 18 were added methanol (3 ml) and 3Npotassium hydroxide (3 ml) and the mixture was stirred at 90° C. for 4hour. The resultant was adjusted to pH 5 by concentrated hydrochloricacid and the precipitated solid was collected by filtration to give 230mg (0.51 mmol) of the titled compound as a pale yellow solid. Yield:95%.

¹H NMR (DMSO-d₆) δ 12.91 (1H, brs), 8.33 (1H, brs), 7.72 (1H, d, J=7.6Hz), 7.50 (2H, m), 7.35 (1H, d, J=7.4 Hz), 6.80 (2H, brs), 4.15 (2H, t,J=6.5 Hz), 4.05 (3H, s), 3.86 (2H, t, J=6.8 Hz), 3.23-3.17 (2H, m),1.78-1.73 (2H, m), 1.66-1.61 (2H, m), 1.41-1.36 (2H, m), 0.91 (3H, t,J=7.3 Hz).

Reference Example 20 Synthesis of2-butoxy-8-methoxy-9-(4-aminobutyl)adenine

To a solution of2-butoxy-8-methoxy-9-{4-(2-hydroxycarbonylbenzamide)butyl}adenine (682mg, 1.5 mmol) obtained in Reference Example 19 in ethanol (20 ml) wasadded hydrazine (3 ml) and the mixture was stirred at 90° C. for 4.5hours. After cooling, the resultant was filtered and the filtrate wasconcentrated under reduced pressure, followed by addition of water andextraction with chloroform (methanol 5%). The organic layer was washedwith water and saturated brine, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give 461 mg (1.5 mmol) of the titledcompound as a pale yellow solid. Yield: 99%.

¹H NMR (DMSO-d₆) δ 6.79 (2H, brs), 4.15 (2H, t, J=6.6 Hz), 4.03 (3H, s),3.82 (2H, t, J=7.0 Hz), 1.73-1.68 (2H, m), 1.67-1.61 (4H, m), 1.43-1.39(2H, m), 1.28-1.23 (2H, m), 0.92 (3H, t, J=7.4 Hz).

Reference Example 21 Synthesis of 3-methoxycarbonylbenzenesulfonylchloride

To a solution of 3-chlorocarbonylbenzenesulfonyl chloride (5.0 g, 21mmol) in THF (100 ml) was added methanol 1.7 ml (42 mmol) and themixture was stirred at room temperature for 13 hours. After the reactionwas completed, the resultant was concentrated under reduced pressure togive 5.14 g (21 mmol) of the titled compound as a pale purple solid.Yield: 100%.

¹H NMR (CDCl₃) δ 8.70 (1H, dd, J=1.4, 1.9 Hz), 8.42 (1H, dt, J=1.4, 7.9Hz), 8.22 (1H, ddd, J=1.2, 1.9, 7.9 Hz), 7.74 (1H, t, J=7.9 Hz), 4.00(3H, s).

Reference Example 22 Synthesis of2-butoxy-8-methoxy-9-[4-(3-methoxycarbonylbenzenesulfonamide)butyl]adenine

To a solution of 2-butoxy-8-methoxy-9-(4-aminobutyl)adenine (440 mg, 1.4mmol) obtained in Reference Example 20 in THF (20 ml) were added3-chlorocarbonylbenzenesulfonyl chloride (502 mg, 2.1 mmol) obtained inReference Example 22 and triethylamine (312 μl, 2.3 mmol) and themixture was stirred at room temperature for 1.5 hour. To the resultantwas added water, and the mixture was concentrated under reduced pressureand purification by silica gel column chromatography to give 724 mg (1.4mmol) of the titled compound as a white solid. Yield: 100%.

¹H NMR (DMSO-d₆) δ 8.30 (1H, dd, J=1.4, 1.7 Hz), 8.15 (1H, ddd, J=1.3,1.4, 7.9 Hz), 8.00 (1H, ddd, J=1.3, 1.7, 7.9 Hz), 7.79 (1H, t, J=5.8Hz), 7.73 (1H, t, J=7.9 Hz), 6.81 (2H, brs), 4.13 (2H, t, J=6.6 Hz),4.02 (3H, s), 3.90 (3H, s), 3.77 (1H, t, J=6.7 Hz), 2.75 (1H, dt, J=5.8,6.6 Hz), 1.65-1.60 (4H, m), 1.42-1.37 (2H, m), 1.27-1.22 (2H, m), 0.89(3H, t, J=7.4 Hz).

Reference Example 23 Synthesis of2-butoxy-8-methoxy-9-[4-(3-hydroxymethylbenzenesulfonamide)butyl]adenine

The titled compound was obtained by the same method as Reference Example6.

¹H NMR (DMSO-d₆) δ 7.74 (1H, s), 7.61-7.62 (1H, m), 7.57-7.56 (2H, m),7.53-7.51 (2H, m), 6.78 (2H, brs), 5.41 (2H, t, J=5.7 Hz), 4.56 (1H, t,J=6.6 Hz), 4.14 (2H, t, J=6.6 Hz), 4.02 (3H, s), 3.76 (2H, t, J=6.6 Hz),2.74 (2H, dt, J=5.8, 6.6 Hz), 1.67-1.63 (4H, m), 1.40-1.36 (2H, m),1.31-1.27 (2H, m), 0.91 (3H, t, J=7.4 Hz).

Reference Example 24 Synthesis of2-butoxy-8-methoxy-9-[4-(3-chloromethylbenzenesulfonamide)butyl]adenine

The titled compound was obtained by the same method as Reference Example7.

¹H NMR (DMSO-d₆) δ 10.36 (1H, br), 7.84 (1H, dd, J=1.4, 1.7 Hz),7.67-7.65 (2H, m), 7.57 (1H, t, J=7.9 Hz), 7.01 (2H, br), 4.86 (2H, s),4.21 (2H, t, J=6.6 Hz), 3.62 (2H, t, J=6.6 Hz), 2.78 (2H, dt, J=5.8, 6.6Hz), 1.65-1.61 (4H, m), 1.41-1.36 (2H, m), 1.35-1.28 (2H, m), 0.91 (3H,t, J=7.4 Hz).

Reference Example 25 Synthesis of2-butoxy-8-methoxy-9-[4-(3-cyanomethylbenzenesulfonamide)butyl]adenine

The titled compound was obtained by the same method as Reference Example8.

¹H NMR (DMSO-d₆) δ 9.83 (1H, s), 7.77 (1H, s), 7.72-7.70 (2H, m),7.59-7.57 (2H, m), 6.40 (2H, br), 4.18 (2H, s), 4.12 (2H, t, J=6.6 Hz),3.60 (2H, t, J=6.6 Hz), 2.76 (2H, dt, J=5.8, 6.6 Hz), 1.66-1.61 (4H, m),1.38-1.30 (4H, m), 0.91 (3H, t, J=7.4 Hz).

Reference Example 26 Synthesis of2-butoxy-8-methoxy-9-[4-(3-methoxycarbonylphenylaminocarbonylamino)butyl]adenine

To a solution of 2-butoxy-8-methoxy-9-(4-aminobutyl)adenine solution(1143 mg, 3.71 mmol) obtained in Reference Example 20 in THF (37 ml) wasadded 3-methoxycarbonylphenyl isocyanate (689 mg, 3.9 mmol) underice-cooling and the mixture was stirred for 5 minutes. The precipitatedsolid was collected by filtration to give 1550 mg (2.4 mmol) of thetitled compound as a white solid. Yield: 86%.

¹H NMR (DMSO-d₆) δ 8.67 (1H, s), 8.10 (1H, dd, J=1.5, 2.2 Hz), 7.57 (1H,ddd, J=1.0, 2.2, 8.2 Hz), 7.48 (1H, ddd, J=1.0, 1.5, 7.6 Hz), 7.34 (1H,dd, J=7.6, 8.2 Hz), 7.68 (2H, brs), 6.17 (1H, t, J=5.7 Hz), 4.15 (2H, t,J=6.6 Hz), 4.05 (3H, s), 3.86 (2H, t, J=6.8 Hz), 3.82 (3H, s), 3.10 (2H,dt, J=5.7, 6.6 Hz), 1.73-1.66 (2H, m), 1.66-1.59 (2H, m), 1.42-1.35 (4H,m), 0.88 (3H, t, J=7.4 Hz).

Reference Example 27 Synthesis of2-butoxy-8-methoxy-9-[4-(3-hydroxymethylphenylaminocarbonylamino)butyl]adenine

The titled compound was obtained by the same method as Reference Example6.

¹H NMR (DMSO-d₆) δ 8.36 (1H, s), 7.32 (1H, s), 7.25 (1H, d, J=8.0 Hz),7.13 (1H, dd, J=7.6, 8.0 Hz), 6.81 (1H, d, J=7.6 Hz), 6.78 (2H, brs),6.08 (1H, t, J=5.7 Hz), 5.11 (1H, t, J=5.7 Hz), 4.41 (2H, d, J=5.7 Hz),4.17 (2H, t, J=6.6 Hz), 4.05 (3H, s), 3.84 (2H, t, J=6.8 Hz), 3.09 (2H,dt, J=5.7, 6.6 Hz), 1.72-1.66 (2H, m), 1.67-1.60 (2H, m), 1.41-1.35 (4H,m), 0.91 (3H, t, J=7.4 Hz).

A example of a pharmaceutical preparation

There was prepared an aerosol containing per 1 g of the aerosol, thecompound of Example 9 (0.641 mg, 0.06%), ethanol (26.816 mg, 2.68%) and1,1,1,2-tetrafluoroethane (972.543 mg, 97.25%).

INDUSTRIAL APPLICABILITY

By the present invention, it has become possible to provide an8-oxoadenine compound effective as a therapeutic or prophylactic agentfor diseases including allergic diseases such as asthma and atopicdermatitis, viral diseases such as herpes and cancers. Further, in acase where the compound of the present invention is externally applied(topical administration) in a form of spray, etc., systemic adverseeffects caused by an interferon inducing activity is suppressed and thestrong effect is exhibited in the applied region.

1-25. (canceled)
 26. A method for treating or preventing at least onedisease chosen from viral diseases, cancers, and allergic diseasescomprising: administering to a patient a therapeutic effective amount of8-oxoadenine compound shown by formula (1):

wherein ring A represents a 6-10 membered aromatic carbocyclic ring or a5-10 membered heteroaromatic ring; R represents a halogen atom, an alkylgroup, a hydroxyalkyl group, a haloalkyl group, an alkoxy group, ahydroxyalkoxy group, a haloalkoxy group, amino group, an alkylaminogroup, a dialkylamino group, or a 4-7 membered cyclic group containingin the ring 1-2 hetero atoms selected from 1-2 nitrogen atoms andoptionally 0-1 oxygen atom or 0-1 sulfur atom; n represents an integerof 0-2, and when n is 2, the Rs may be the same or different; Z¹represents a substituted or unsubstituted alkylene group or asubstituted or unsubstituted cycloalkylene group; X² represents oxygenatom, sulfur atom, SO₂, NR⁵, CO, CONR⁵, NR⁵CO, SO₂NR⁵, NR⁵SO₂, NR⁵CONR⁶or NR⁵CSNR⁶ (in which R⁵ and R⁶ are each independently hydrogen atom, asubstituted or unsubstituted alkyl group, or a substituted orunsubstituted cycloalkyl group); Y¹, Y² and Y³ represent eachindependently a single bond or an alkylene group; X¹ represents oxygenatom, sulfur atom, SO₂, NR⁴ (wherein R⁴ is hydrogen atom or an alkylgroup) or a single bond; R² represents hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkenyl group,a substituted or unsubstituted alkynyl group or a substituted orunsubstituted cycloalkyl group; and R¹ represents hydrogen atom, hydroxygroup, an alkoxy group, an alkoxycarbonyl group, a haloalkyl group, ahaloalkoxy group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group or a substituted orunsubstituted cycloalkyl group, or its pharmaceutically acceptable salt.27. The method according to claim 1, wherein the at least one disease ischosen from asthma, allergic rhinitis, allergic conjunctivitis, atopicdermatosis, cancer, infection with hepatitis B virus, infection withhepatitis C virus, infection with HIV, infection with human papillomavirus, bacterial infections, and dermatitis.
 28. The method according toclaim 1, wherein the at least one disease is asthma or allergicrhinitis.
 29. A method for modulating immune response comprisingadministering to a patient a therapeutically effective amount of8-oxoadenine compound shown by formula (1):

wherein ring A represents a 6-10 membered aromatic carbocyclic ring or a5-10 membered heteroaromatic ring; R represents a halogen atom, an alkylgroup, a hydroxyalkyl group, a haloalkyl group, an alkoxy group, ahydroxyalkoxy group, a haloalkoxy group, amino group, an alkylaminogroup, a dialkylamino group, or a 4-7 membered cyclic group containingin the ring 1-2 hetero atoms selected from 1-2 nitrogen atoms andoptionally 0-1 oxygen atom or 0-1 sulfur atom; n represents an integerof 0-2, and when n is 2, the R⁵ may be the same or different; Z¹represents a substituted or unsubstituted alkylene group or asubstituted or unsubstituted cycloalkylene group; X² represents oxygenatom, sulfur atom, SO₂, NR⁵, CO, CONR⁵, NR⁵CO, SO₂NR⁵, NR⁵SO₂, NR⁵CONR⁶or NR⁵CSNR⁶ (in which R⁵ and R⁶ are each independently hydrogen atom, asubstituted or unsubstituted alkyl group, or a substituted orunsubstituted cycloalkyl group); Y¹, Y² and Y³ represent eachindependently a single bond or an alkylene group; X¹ represents oxygenatom, sulfur atom, SO₂, NR⁴ (wherein R⁴ is hydrogen atom or an alkylgroup) or a single bond; R² represents hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkenyl group,a substituted or unsubstituted alkynyl group or a substituted orunsubstituted cycloalkyl group; and R¹ represents hydrogen atom, hydroxygroup, an alkoxy group, an alkoxycarbonyl group, a haloalkyl group, ahaloalkoxy group, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group or a substituted orunsubstituted cycloalkyl group, or its pharmaceutically acceptable salt.30. The method according to claim 1, wherein: ring A represents a 6-10membered aromatic carbocyclic ring, or a 5-10 membered heteroaromaticring containing 1-4 hetero atoms selected from 0-4 nitrogen atoms, 0-2oxygen atoms, and 0-2 sulfur atoms; R represents a halogen atom, analkyl group of 1-6 carbons, a hydroxyalkyl group of 1-6 carbons, ahaloalkyl group of 1-6 carbons, an alkoxy group of 1-6 carbons, ahydroxyalkoxy group of 1-6 carbons, a haloalkoxy group of 1-6 carbons,amino group, an alkylamino group of 1-6 carbons, a dialkylamino group inwhich each alkyl moiety has 1-6 carbons, or a 4-7 membered cyclic groupcontaining in the ring 1-2 hetero atoms selected from 1-2 nitrogen atomsand optionally 0-1 oxygen atom or 0-1 sulfur atom; Z¹ represents analkylene group of 1-6 carbons or a cycloalkylene group of 3-8 carbons,which is optionally substituted by hydroxy group; X² represents oxygenatom, sulfur atom, SO₂, NR⁵, CO, CONR⁵, NR⁵CO, SO₂NR⁵, NR⁵SO₂, NR⁵CONR⁶or NR⁵CSNR⁶ (in which R⁵ and R⁶ are each independently hydrogen atom, asubstituted or unsubstituted alkyl group of 1-6 carbons, or asubstituted or unsubstituted cycloalkyl group of 3-8 carbons, whereinthe substituents of the alkyl group or cycloalkyl group are selectedfrom a halogen atom, hydroxy group, an alkoxy group of 1-6 carbons,carboxy group, an alkoxycarbonyl group of 2-5 carbons, carbamoyl group,amino group, an alkylamino group of 1-6 carbons, an dialkylamino groupin which each alkyl moiety has 1-6 carbons, a cyclic group, andtetrazolyl group which may be substituted by an alkyl group of 1-6carbons); Y¹, Y² and Y³ represent each independently a single bond or analkylene group of 1-6 carbons; R² represents a substituted orunsubstituted alkyl group of 1-6 carbons, a substituted or unsubstitutedalkenyl group of 2-6 carbons, a substituted or unsubstituted alkynylgroup of 2-6 carbons, or a substituted or unsubstituted cycloalkyl groupof 3-8 carbons (wherein the substituent in the alkyl group, alkenylgroup and alkynyl group is selected from a halogen atom, hydroxy group,an alkoxy group of 1-6 carbons, an acyloxy group of 2-10 carbonsselected from the group consisting of a substituted or unsubstitutedalkylcarbonyloxy group of 2-5 carbons, a substituted or unsubstitutedalkenylcarbonyloxy group of 2-5 carbons, a substituted or unsubstitutedalkynylcarbonyloxy group of 2-5 carbons, a substituted or unsubstitutedarylcarbonyloxy group and a substituted or unsubstitutedheteroarylcarbonyloxy group, amino group, an alkylamino group of 1-6carbons, a dialkylamino group in which the each alkyl moiety has 1-6carbons, and a cyclic group); and R¹ represents hydrogen atom, hydroxygroup, an alkoxy group of 1-6 carbons, an alkoxycarbonyl group of 2-5carbons, a haloalkyl group of 1-6 carbons, a haloalkoxy group of 1-6carbons, a substituted or unsubstituted aryl group of 6-10 carbons, asubstituted or unsubstituted 5-10 membered heteroaryl group containing1-4 hetero atoms selected from 0-4 nitrogen atoms, 0-2 oxygen atoms and0-2 sulfur atoms, or a substituted or unsubstituted cycloalkyl group of3-8 carbons; and the said substituent in the aryl group, the heteroarylgroup, and the cycloalkyl group is selected from a halogen atom, hydroxygroup, an alkyl group of 1-6 carbons, a haloalkyl group of 1-6 carbons,an alkoxy group of 1-6 carbons, a haloalkoxy group of 1-6 carbons, analkylcarbonyl group of 2-5 carbons, amino group, an alkylamino group of1-6 carbons and a dialkylamino group (wherein the each alkyl group has1-6 carbons), and the said cyclic group represents a 4-7 memberedsaturated cyclic group containing in the ring 1-2 hetero atoms selectedfrom 1-2 nitrogen atoms and optionally 0-1 oxygen atom or 0-1 sulfuratom, which may be substituted with a halogen atom, hydroxy group, oxogroup, an alkyl group of 1-6 carbons, an alkoxy group of 1-6 carbons, analkylcarbonyl group of 2-5 carbons, or an alkoxycarbonyl group of 2-5carbons, or its pharmaceutically acceptable salt.
 31. The methodaccording to claim 1, wherein X² is oxygen atom, sulfur atom, NR⁵, SO₂,NR⁵SO₂, or NR⁵CONR⁶.
 32. The method according to claim 1, wherein Y³ isa single bond, methylene, or ethylene.
 33. The method according to claim1, wherein Z¹ is a straight chained alkylene group of 1-6 carbons whichmay be substituted with hydroxy group.
 34. The method according to claim1, wherein X¹ is oxygen atom or sulfur atom.
 35. The method according toclaim 1, wherein Y¹ is a single bond or an alkylene group of 1-6carbons.
 36. The method according to claim 1, wherein R¹ is hydrogenatom, an alkoxycarbonyl group, hydroxy group, or an alkoxy group. 37.The method according to claim 1, wherein in the formula (1), a groupshown by the formula (2):

(wherein ring A, R, n, Y³ and R² have the same meaning as in claim 1) isa group shown by the formula (3) or the formula (4):

(wherein R, n and R² have the same meaning as in claim 1, and R³ ishydrogen atom or an alkyl group).
 38. The method according to claim 1,wherein R² is methyl group or an alkyl group of 2-6 carbons substitutedby a dialkylamino group or a cyclic group.
 39. The method according toclaim 1, wherein R³ is hydrogen atom.
 40. The method according to claim1, wherein the compound shown by formula (1) is chosen from: Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate,its pharmaceutically acceptable salts, Methyl[3-({[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl][3-(dimethylamino)-2,2-dimethylpropyl]amino}methyl)phenyl]acetate,its pharmaceutically acceptable salts, Methyl(3-{[[4-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)butyl](2-morpholin-4-ylethyl)amino]methyl}phenyl)acetate,its pharmaceutically acceptable salts, and Methyl(3-{[[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenyl)acetate,and its pharmaceutically acceptable salts.